Breast cancer

Breast cancer is an uncontrolled growth of breast cells. To better understand breast cancer, it helps to understand how any cancer can develop.

Cancer occurs as a result of mutations, or abnormal changes, in the genes responsible for regulating the growth of cells and keeping them healthy. The genes are in each cell’s nucleus, which acts as the “control room” of each cell. Normally, the cells in our bodies replace themselves through an orderly process of cell growth: healthy new cells take over as old ones die out. But over time, mutations can “turn on” certain genes and “turn off” others in a cell. That changed cell gains the ability to keep dividing without control or order, producing more cells just like it and forming a tumor.

A tumor can be benign (not dangerous to health) or malignant (has the potential to be dangerous). Benign tumors are not considered cancerous: their cells are close to normal in appearance, they grow slowly, and they do not invade nearby tissues or spread to other parts of the body. Malignant tumors are cancerous. Left unchecked, malignant cells eventually can spread beyond the original tumor to other parts of the body.

The term “breast cancer” refers to a malignant tumor that has developed from cells in the breast. Usually breast cancer either begins in the cells of the lobules, which are the milk-producing glands, or the ducts, the passages that drain milk from the lobules to the nipple. Less commonly, breast cancer can begin in the stromal tissues, which include the fatty and fibrous connective tissues of the breast.

Over time, cancer cells can invade nearby healthy breast tissue and make their way into the underarm lymph nodes, small organs that filter out foreign substances in the body. If cancer cells get into the lymph nodes, they then have a pathway into other parts of the body. The breast cancer’s stage refers to how far the cancer cells have spread beyond the original tumor.

Breast cancer is always caused by a genetic abnormality (a “mistake” in the genetic material). However, only 5-10% of cancers are due to an abnormality inherited from your mother or father. About 90% of breast cancers are due to genetic abnormalities that happen as a result of the aging process and the “wear and tear” of life in general.

While there are steps every person can take to help the body stay as healthy as possible (such as eating a balanced diet, not smoking, limiting alcohol, and exercising regularly), breast cancer is never anyone's fault. Feeling guilty, or telling yourself that breast cancer happened because of something you or anyone else did, is not productive.

Symptoms of Breast Cancer

Initially, breast cancer may not cause any symptoms. A lump may be too small for you to feel or to cause any unusual changes you can notice on your own. Often, an abnormal area turns up on a screening mammogram (x-ray of the breast), which leads to further testing.

In some cases, however, the first sign of breast cancer is a new lump or mass in the breast that you or your doctor can feel. A lump that is painless, hard, and has uneven edges is more likely to be cancer. But sometimes cancers can be tender, soft, and rounded. So it's important to have anything unusual checked by your doctor.

According to the American Cancer Society, any of the following unusual changes in the breast can be a symptom of breast cancer:

• swelling of all or part of the breast
• skin irritation or dimpling
• breast pain
• nipple pain or the nipple turning inward
• redness, scaliness, or thickening of the nipple or breast skin
• a nipple discharge other than breast milk
• a lump in the underarm area

These changes also can be signs of less serious conditions that are not cancerous, such as an infection or a cyst. It’s important to get any breast changes checked out promptly by a doctor

Stages of Breast Cancer

Stage	Definition
Stage 0	Cancer cells remain inside the breast duct, without invasion into normal adjacent breast tissue.
Stage I	Cancer is 2 centimeters or less and is confined to the breast (lymph nodes are clear).
Stage IIA	No tumor can be found in the breast, but cancer cells are found in the axillary lymph nodes (the lymph nodes under the arm) OR the tumor measures 2 centimeters or smaller and has spread to the axillary lymph nodes OR the tumor is larger than 2 but no larger than 5 centimeters and has not spread to the axillary lymph nodes.
Stage IIB	The tumor is larger than 2 but no larger than 5 centimeters and has spread to the axillary lymph nodes OR the tumor is larger than 5 centimeters but has not spread to the axillary lymph nodes.
Stage IIIA	No tumor is found in the breast. Cancer is found in axillary lymph nodes that are sticking together or to other structures, or cancer may be found in lymph nodes near the breastbone OR the tumor is any size. Cancer has spread to the axillary lymph nodes, which are sticking together or to other structures, or cancer may be found in lymph nodes near the breastbone.
Stage IIIB	The tumor may be any size and has spread to the chest wall and/or skin of the breast AND may have spread to axillary lymph nodes that are clumped together or sticking to other structures, or cancer may have spread to lymph nodes near the breastbone. Inflammatory breast cancer is considered at least stage IIIB.
Stage IIIC	There may either be no sign of cancer in the breast or a tumor may be any size and may have spread to the chest wall and/or the skin of the breast AND the cancer has spread to lymph nodes either above or below the collarbone AND the cancer may have spread to axillary lymph nodes or to lymph nodes near the breastbone.
Stage IV	The cancer has spread — or metastasized — to other parts of the body.

By now you may be familiar with the statistic that says 1 in 8 women will develop invasive breast cancer. Many people misinterpret this to mean that, on any given day, they and the women they know have a 1-in-8 risk of developing the disease. That’s simply not true.
In reality, about 1 in 8 women in the United States — 12%, or about 12 out of every 100 — can expect to develop breast cancer over the course of an entire lifetime. In the U.S., an average lifetime is about 80 years. So, it’s more accurate to say that 1 in 8 women in the U.S. who reach the age of 80 can expect to develop breast cancer. In each decade of life, the risk of getting breast cancer is actually lower than 12% for most women.
People tend to have very different ways of viewing risk. For you, a 1-in-8 lifetime risk may seem like a high likelihood of getting breast cancer. Or you may turn this around and reason that there is a 7-in-8, or 87.5%, chance you will never get breast cancer, even if you live to age 80. How you view risk often depends on your individual situation — for example, whether you or many women you know have had breast cancer, or you have reason to believe you are at higher-than-normal risk for the disease — and your usual way of looking at the world.
Even though studies have found that women have a 12% lifetime risk of developing breast cancer, your individual risk may be higher or lower than that. Individual risk is affected by many different factors, such as family history, reproductive history, lifestyle, environment, and others.
This section is designed to help you better understand breast cancer risk and some of the factors that can increase risk.

A “risk factor” is anything that increases your risk of developing breast cancer. Many of the most important risk factors for breast cancer are beyond your control, such as age, family history, and medical history. However, there are some risk factors you can control, such as weight, physical activity, and alcohol consumption.

Be sure to talk with your doctor about all of your possible risk factors for breast cancer. There may be steps you can take to lower your risk of breast cancer, and your doctor can help you come up with a plan. Your doctor also needs to be aware of any other risk factors beyond your control, so that he or she has an accurate understanding of your level of breast cancer risk. This can influence recommendations about breast cancer screening — what tests to have and when to start having them.

Risk factors you can control

Weight. Being overweight is associated with increased risk of breast cancer, especially for women after menopause. Fat tissue is the body’s main source of estrogen after menopause, when the ovaries stop producing the hormone. Having more fat tissue means having higher estrogen levels, which can increase breast cancer risk.

Diet. Diet is a suspected risk factor for many types of cancer, including breast cancer, but studies have yet to show for sure which types of foods increase risk. It’s a good idea to restrict sources of red meat and other animal fats (including dairy fat in cheese, milk, and ice cream), because they may contain hormones, other growth factors, antibiotics, and pesticides. Some researchers believe that eating too much cholesterol and other fats are risk factors for cancer, and studies show that eating a lot of red and/or processed meats is associated with a higher risk of breast cancer. A low-fat diet rich in fruits and vegetables is generally recommended. For more information, visit our page on healthy eating to reduce cancer risk in the Nutrition section.

Exercise. Evidence is growing that exercise can reduce breast cancer risk. The American Cancer Society recommends engaging in 45-60 minutes of physical exercise 5 or more days a week.

Alcohol consumption. Studies have shown that breast cancer risk increases with the amount of alcohol a woman drinks. Alcohol can limit your liver’s ability to control blood levels of the hormone estrogen, which in turn can increase risk.

Smoking. Smoking is associated with a small increase in breast cancer risk.

Exposure to estrogen. Because the female hormone estrogen stimulates breast cell growth, exposure to estrogen over long periods of time, without any breaks, can increase the risk of breast cancer. Some of these risk factors are under your control, such as:

• taking combined hormone replacement therapy (estrogen and progesterone; HRT) for several years or more, or taking estrogen alone for more than 10 years
• being overweight
• regularly drinking alcohol

Recent oral contraceptive use. Using oral contraceptives (birth control pills) appears to slightly increase a woman’s risk for breast cancer, but only for a limited period of time. Women who stopped using oral contraceptives more than 10 years ago do not appear to have any increased breast cancer risk.

Stress and anxiety. There is no clear proof that stress and anxiety can increase breast cancer risk. However, anything you can do to reduce your stress and to enhance your comfort, joy, and satisfaction can have a major effect on your quality of life. So-called “mindful measures” (such as meditation, yoga, visualization exercises, and prayer) may be valuable additions to your daily or weekly routine. Some research suggests that these practices can strengthen the immune system.

Risk factors you can’t control

Gender. Being a woman is the most significant risk factor for developing breast cancer. Although men can get breast cancer, too, women’s breast cells are constantly changing and growing, mainly due to the activity of the female hormones estrogen and progesterone. This activity puts them at much greater risk for breast cancer.

Age. Simply growing older is the second biggest risk factor for breast cancer. From age 30 to 39, the risk is 1 in 233, or .43%. That jumps to 1 in 27, or almost 4%, by the time you are in your 60s.

Family history of breast cancer. If you have a first-degree relative (mother, daughter, sister) who has had breast cancer, or you have multiple relatives affected by breast or ovarian cancer (especially before they turned age 50), you could be at higher risk of getting breast cancer.

Personal history of breast cancer. If you have already been diagnosed with breast cancer, your risk of developing it again, either in the same breast or the other breast, is higher than if you never had the disease.

Race. White women are slightly more likely to develop breast cancer than are African American women. Asian, Hispanic, and Native American women have a lower risk of developing and dying from breast cancer.

Radiation therapy to the chest. Having radiation therapy to the chest area as a child or young adult as treatment for another cancer significantly increases breast cancer risk. The increase in risk seems to be highest if the radiation was given while the breasts were still developing (during the teen years).

Breast cellular changes. Unusual changes in breast cells found during a breast biopsy (removal of suspicious tissue for examination under a microscope) can be a risk factor for developing breast cancer. These changes include overgrowth of cells (called hyperplasia) or abnormal (atypical) appearance.

Exposure to estrogen. Because the female hormone estrogen stimulates breast cell growth, exposure to estrogen over long periods of time, without any breaks, can increase the risk of breast cancer. Some of these risk factors are not under your control, such as:

• starting menstruation (monthly periods) at a young age (before age 12)
• going through menopause (end of monthly cycles) at a late age (after 55)
• exposure to estrogens in the environment (such as hormones in meat or pesticides such as DDT, which produce estrogen-like substances when broken down by the body)

Pregnancy and breastfeeding. Pregnancy and breastfeeding reduce the overall number of menstrual cycles in a woman’s lifetime, and this appears to reduce future breast cancer risk. Women who have never had a full-term pregnancy, or had their first full-term pregnancy after age 30, have an increased risk of breast cancer. For women who do have children, breastfeeding may slightly lower their breast cancer risk, especially if they continue breastfeeding for 1 1/2 to 2 years. For many women, however, breastfeeding for this long is neither possible nor practical.

DES exposure. Women who took a medication called diethylstilbestrol (DES), used to prevent miscarriage from the 1940s through the 1960s, have a slightly increased risk of breast cancer. Women whose mothers took DES during pregnancy may have a higher risk of breast cancer as well.

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HIV Time To Concern

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world.

HIV infection in humans is considered pandemic by the World Health Organization (WHO). Nevertheless, complacency about HIV may play a key role in HIV risk. From its discovery in 1981 to 2006, AIDS killed more than 25 million people. HIV infects about 0.6% of the world's population. In 2009, AIDS claimed an estimated 1.8 million lives, down from a global peak of 2.1 million in 2004. Approximately 260,000 children died of AIDS in 2009. A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and exacerbating the burden of poverty. In 2005, it was estimated that HIV would infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans. Treatment with antiretroviral drugs reduces both the mortality and the morbidity of HIV infection. Although antiretroviral medication is still not universally available, expansion of antiretroviral therapy programmes since 2004 has helped to turn the tide of AIDS deaths and new infections in many parts of the world. Intensified awareness and preventive measures, as well as the natural course of the epidemic, have also played a role. Nevertheless, an estimated 2.6 million people were newly infected in 2009.

HIV infects vital cells in the human immune system such as helper T cells (specifically CD4⁺ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4⁺ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4⁺ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4⁺ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.

Most untreated people infected with HIV-1 eventually develop AIDS. These individuals mostly die from opportunistic infections or malignancies associated with the progressive failure of the immune system. HIV progresses to AIDS at a variable rate affected by viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV infection: some will have progressed much sooner, and some will take much longer. Treatment with anti-retrovirals increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy was estimated to be more than 5 years as of 2005. Without antiretroviral therapy, someone who has AIDS typically dies within a year.

Classification

Comparison of HIV species
Species	Virulence	Infectivity	Prevalence	Inferred origin
HIV-1	High	High	Global	Common Chimpanzee
HIV-2	Lower	Low	West Africa	Sooty Mangabey

 HIV is a member of the genus Lentivirus, part of the family of Retroviridae. Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host co-factors. Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that begin the replication cycle anew.

Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both LAV and HTLV-III. It is more virulent, more infective, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2 compared to HIV-1 implies that fewer of those exposed to HIV-2 will be infected per exposure. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.

Signs and symptoms 

A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4⁺ T cell count (cells per µL) HIV RNA copies per mL of plasma

Infection with HIV-1 is associated with a progressive decrease of the CD4⁺ T cell count and an increase in viral load, the level of HIV in the blood. The stage of infection can be determined by measuring the patient's CD4⁺ T cell count and viral load.

The stages of HIV infection are acute infection (also known as primary infection), latency and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts (fewer than 200 per microliter), various opportunistic infections, cancers and other conditions.

A small percentage of HIV-1 infected individuals retain high levels of CD4+ T-cells without antiretroviral therapy. However, most have detectable viral load and will eventually progress to AIDS without treatment, albeit more slowly than others. These individuals are classified as HIV controllers or long-term nonprogressors (LTNP). People who maintain CD4+ T cell counts and also have low or clinically undetectable viral load without anti-retroviral treatment are known as elite controllers or elite suppressors (ES).

Acute infection

Infection with HIV generally occurs by introduction of bodily fluids from an infected person into the body of an uninfected person. A period of rapid viral replication ensues, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.

This response is accompanied by a marked drop in the numbers of circulating CD4⁺ T cells. This acute viremia is associated in virtually all patients with the activation of CD8⁺ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8⁺ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4⁺ T cell counts rebound. A good CD8⁺ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.

During this period (usually 2–4 weeks post-exposure) most individuals (80 to 90%) develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophageal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week.

Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose HIV infection, as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.

Chronic infection

A strong immune defense reduces the number of viral particles in the blood stream, marking the start of secondary or chronic HIV infection. The secondary stage of HIV infection can vary between two weeks and 20 years. During this phase of infection, HIV is active within lymph nodes, which typically become persistently swollen, in response to large amounts of virus that become trapped in the follicular dendritic cells (FDC) network. The surrounding tissues that are rich in CD4⁺ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4⁺ CD45RO⁺ T cells carry most of the proviral load.

During this stage of infection early initiation of antiretroviral therapy significantly improves survival, as compared with deferred therapy.

AIDS

When CD4⁺ T cell numbers decline below a critical level of 200 cells per µL, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations.

Common opportunistic infections and tumors, most of which are normally controlled by robust CD4⁺ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma.

Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.

Transmission

Estimated per-act risk for acquisition of HIV by exposure route
Exposure Route	Estimated infections per 10,000 exposures to an infected source
Blood transfusion	9,000
Childbirth	2,500
Needle-sharing injection drug use	67
Percutaneous needle stick	30
Receptive anal intercourse (2009 and 2010 studies)	170‡ [30–890] / 143 [48-285]
Receptive anal intercourse (based on data of a 1992 study)	50
Insertive anal intercourse for uncircumcised men (2010 study)	62a [7-168]
Insertive anal intercourse for circumcised men (2010 study)	11a [2–24]
Insertive anal intercourse (based on data of a 1992 study)	6.5
Low-income country female-to-male	38‡ [13–110]
Low-income country male-to-female	30‡ [14–63]
Receptive penile-vaginal intercourse	10
Insertive penile-vaginal intercourse	5
Fellating a man	1†b
Man being fellated	0.5†b
The data shown represents the rate of transmission when condoms were not used. Note that risk rates may change due to other factors such as commercial sex exposure, phase of HIV infection, presence or history of genital ulcers, and national income levels.
Bracketed values represent 95% confidence interval † "best-guess estimate" ‡ Pooled transmission probability estimate
a Other studies found insufficient evidence that male circumcision protects against HIV infection among men who have sex with men
b Oral trauma, sores, inflammation, concomitant sexually transmitted infections, ejaculation in the mouth, and systemic immune suppression may increase HIV transmission rate.

Three main transmission routes for HIV have been identified. HIV-2 is transmitted much less frequently by the mother-to-child and sexual route than HIV-1.

Sexual

The majority of HIV infections are acquired through unprotected sexual relations. Complacency about HIV plays a key role in HIV risk. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another. In high-income countries, the risk of female-to-male transmission is 0.04% per act and male-to-female transmission is 0.08% per act. For various reasons, these rates are 4 to 10 times higher in low-income countries. The rate for receptive anal intercourse is much higher, 1.7% per act.

A 1999 meta-analysis of studies of condom use showed that the consistent use of latex condoms reduces the risk of sexual transmission of HIV by about 85%.However, spermicide may actually increase the transmission rate.

Randomized, controlled trials in which uncircumcised men were randomly assigned to be medically circumcised in sterile conditions and given counseling and other men were not circumcised have been conducted in South Africa, Kenya, and Uganda showing reductions in female-to-male sexual HIV transmission of 60%, 53%, and 51%, respectively. As a result, a panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men." Among men who have sex with men, there is insufficient evidence that male circumcision protects against HIV infection or other Sexually Transmitted Infections.

Studies of HIV among women having undergone female genital cutting (FGC) have reported mixed results, but with some evidence of increased risk of transmission. Programmes that aim to encourage sexual abstinence while also encouraging and teaching safer sex strategies for those who are sexually active can reduce short- and long-term HIV risk behaviour among young people in high-income countries, according to a 2007 Cochrane Review of studies.

Blood products

In general, if infected blood comes into contact with any open wound, HIV may be transmitted. This transmission route can account for infections in intravenous drug users, hemophiliacs, and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. Health care workers such as nurses, laboratory workers, and doctors have also been infected, although this occurs more rarely. Since transmission of HIV by blood became known medical personnel are required to protect themselves from contact with blood by the use of universal precautions. People giving and receiving tattoos, piercings, and scarification procedures can also be at risk of infection.

HIV has been found at low concentrations in the saliva, tears, and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible. It is not possible for mosquitoes to transmit HIV.

Mother-to-child

The transmission of the virus from the mother to the child can occur in utero (during pregnancy), intrapartum (at childbirth), or via breast feeding. In the absence of treatment, the transmission rate up to birth between the mother and child is around 25%. However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as one percent. Postnatal mother-to-child transmission may be largely prevented by complete avoidance of breast feeding; however, this has significant associated morbidity. Exclusive breast feeding and the provision of extended antiretroviral prophylaxis to the infant are also efficacious in avoiding transmission. UNAIDS estimate that 430,000 children were infected worldwide in 2008 (19% of all new infections), primarily by this route, and that a further 65,000 infections were averted through the provision of antiretroviral prophylaxis to HIV-positive women.

Multiple infection

Unlike some other viruses, infection with HIV does not provide immunity against additional infections, in particular, in the case of more genetically distant viruses. Both inter- and intra-clade multiple infections have been reported, and even associated with more rapid disease progression. Multiple infections are divided into two categories depending on the timing of the acquisition of the second strain. Coinfection refers to two strains that appear to have been acquired at the same time (or too close to distinguish). Reinfection (or superinfection) is infection with a second strain at a measurable time after the first. Both forms of dual infection have been reported for HIV in both acute and chronic infection around the world.

Prevention

There is currently no publicly available vaccine for HIV or AIDS.^[68][69][70] However, a vaccine that is a combination of two previously unsuccessful vaccine candidates (ALVAC-HIV and AIDSVAX) was reported in September 2009 to have resulted in a 30% reduction in infections in a trial conducted in Thailand. Further trials of the vaccine are ongoing. Additionally, a course of antiretroviral treatment administered immediately after exposure, referred to as post-exposure prophylaxis, is believed to reduce the risk of infection if begun as quickly as possible. In July 2010, a vaginal gel containing tenofovir, a reverse transcriptase inhibitor, was shown to reduce HIV infection rates by 39 percent in a trial conducted in South Africa.

Early treatment of HIV-infected people with antiretrovirals protected 96% of partners from infection.

Replication cycle

Entry to the cell

HIV enters macrophages and CD4⁺ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the cell membrane and the release of the HIV capsid into the cell.

Entry to the cell begins through interaction of the trimeric envelope complex and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface. gp120 binds to integrin α₄β₇ activating LFA-1 the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors.

The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell. During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T-cells when the virus is captured in the mucosa by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.

Replication and transcription

Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.

Reverse transcription of the HIV genome into double strand DNA

This integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is upregulated when T-cells become activated. This means that those cells most likely to be killed by HIV are those currently fighting infection.

During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins Tat (which encourages new virus production) and Rev. As the newly produced Rev protein accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced. At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.

HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA, whereas HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).

Assembly and release

The final step of the viral cycle, assembly of new HIV-1 virons, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. Maturation occurs either in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion. This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.

Genetic variability

HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of about 10¹⁰ virions every day, coupled with a high mutation rate of approximately 3 x 10⁻⁵ per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.

This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day. This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes. This recombination is most obvious when it occurs between subtypes.

The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus, which is present at high levels in the host's blood but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans.

In contrast, when these strains infect species that have not adapted to SIV ("heterologous" hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection. Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host. Both SIVcpz and HIV-1 appear to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus. Both viruses have also lost a function of the Nef gene that is present in most SIVs; without this function, T cell depletion is more likely, leading to immunodeficiency.

Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct. The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes. The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009. The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.

The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsmm.

Diagnosis

Many HIV-positive people are unaware that they are infected with the virus. For example, less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results. Again, this proportion is even lower in rural health facilities. Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.

HIV-1 testing consists of initial screening with an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person.

Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate Western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations. In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection.

Modern HIV testing is extremely accurate. The chance of a false-positive result in the two-step testing protocol is estimated to be 0.0004% to 0.0007% in the general U.S. population.

Screening

President of South Africa, Jacob Zuma is launching HIV testing for secondary schools in March 2011 on weekends and holidays. The government believes that knowing HIV status could allow early access to life-saving treatment and help prevent the spread of the infection. But critics warn of psychological harm for young people from positive test results.

HIV Medicine

Current Treatments
There is no cure or vaccine for HIV, however, it is important to help a body living with the stress of HIV to try and mend itself as much as possible. The first line of defense is a diet that promotes lean muscle mass and prevents weight loss. It is important to weigh in about three times a week and test lean-muscle mass at least once a year (Cohen 1998).

Obviously, diet and exercise aren’t enough. Today we fight HIV with three different classes of HIV medicine:

• Reverse transcriptase nucleoside inhibitors (nucleoside analogs)
• Protease inhibitors
• Non-nucleoside reverse transciptase inhibitors

Two more classes are currently under development:
• Integrase inhibitors
• Fusion inhibitors

Integrase Inhibitors block HIV replication in mid-phase by binding HIV integrase. By blocking this step, HIV is unable to enter the T4 cell genetic code, therefore stopping the HIV replication process from proceeding.

Fusion Inhibitors block HIV in early phase by blocking HIV fusion to the T4 cell membrane (Senechek 1997).

Nucleoside analogs (drugs) block HIV replication in its “early phase” replication by binding to HIV reverse transcriptase, and through chain termination in “early” and “mid phase” replication (Senechek 1997).

An example of a nucleoside analog is Abacavir, 1592, 1592U89. Abacavir is the first successful HIV medicine made from the nucleoside guanine. Its structure is a carbocylic guanine nucleoside. Research currently recommends 300 mg twice a day. Side effects include nausea, headache, and diarrhea (Senechek 1997).

Protease inhibitors block HIV replication in late phase by binding to HIV protease, which stops maturation of newly formed HIV viruses (Senechek 1997).

Examples of protease inhibitors include: Saquinavir, Invirase, and Saquinavir Mesylate. Saquinavir inhibits HIV protease, which stops HIV maturation. The dose comes in 200 mg capsules, and the recommended amount is 1200 to 1800 mg three times a day with food. Side effects include nausea, bloating, diarrhea, and a headache. Unfortunately, only about four percent of the drug is actually absorbed by the body (Senechek 1997).

Reverse transcriptase non-nucleoside inhibitors also block HIV in early phase by binding to reverse transcriptase (Senechek 1997).

An example of a reverse transcriptase non-nucleoside inhibitor is Delavirdine, (also called Rescriptor and DLV). Delavirdine is similar to Nevirapine. Four 100 mg tablets are recommended three times a day, but scientists are researching whether Delavirdine at 400 mg three times a day may prevent people from developing AZT resistance. Side effects can include a rash, Stevens-Johnson Syndrome (a life-threatening allergic reaction to drugs), nausea, and diarrhea (Senechek 1997).

The only treatments available to patients today are designed to stop the virus from replicating. This is because HIV is a highly expedient replicating virus. Billions of new HIV particles are produced each day in the cells of an infected person (Senechek 1997).

Antiretroviral Therapy

Doctors determine how and when a patient should be treated based on symptoms of HIV disease or a deficit of CD4 cells (for example, less than 200). Regardless of CD4 count, however, treatment is recommended for all pregnant patients, patients with HIV-associated nephropathy (a kidney disorder), or patients who need treatment for hepatitis B. (Munk 2008)

The goals of retroviral therapy include the following:
• To reduce viral load as much as possible
• To restore or preserve the immune system
• To improve the patient’s quality of life
• To reduce sickness and death due to HIV
Steps to take in order to achieve these goals include:
• To take medication correctly and consistently
• To think about research and future regimens when choosing drugs and keep future options open

The Issue of Drug Resistance

Unfortunately, no antiretroviral (ARV) drug is resistance-proof. This means HIV drug resistance will naturally evolve whenever it is confronted by the selective pressure from drugs or from the immune system. How does resistance develop? Often it is because the patient isn’t compliant; they take their medications randomly, creating a foothold for HIV to gain strength.

The problem grows when a person with a now ARV-resistant strain infects someone new. As the new resistant virus spreads, they are virtually untreatable. Transmission of HIV resistance strains is of increasing concern in countries where ARV is widely used. (Chan 2008)

Who Gets Medication?

People with 50,000 viruses per ml of blood should get medication, but with over 42 million people living with HIV/AIDS, 74 percent of which live in sub-Saharan Africa (Jasper 2008) clearly, not everyone will receive the treatment they need. Until these medications can be made more cheaply, those living in third world countries will have to depend on the compassion of foundations and individuals to supply the help they need.