Wednesday, 07 Dec, 2016
WORLD AIDS DAY :
“CELEBRATED ON 1ST DECEMBER OF EVERY YEAR .”
AIDS, by name of acquired immunodeficiency syndrome , transmissible disease of the immune system caused by the human immunodeficiency virus (HIV). HIV is a lent virus (literally meaning “slow virus”; a member of the retrovirus family) that slowly attacks and destroys the immune system, the body’s defence against infection, leaving an individual vulnerable to a variety of other infections and certain malignancies that eventually cause death. AIDS is the final stage of HIV infection, during which time fatal infections and cancers frequently arise.
The emergence of AIDS
On June 5, 1981, the U.S. Centres for Disease Control and Prevention (CDC) published a report describing a rare lung infection known as Pneumocystis carinii pneumonia in five homosexual men in Los Angeles. Expert review of the cases suggested that the disease likely was acquired through sexual contact and that it appeared to be associated with immune dysfunction caused by exposure to some factor that predisposed the affected individuals to opportunistic infection. The following month the CDC published a report describing an outbreak of cases of a rare cancer called Kaposi sarcoma in homosexual men in New York City and San Francisco. The report noted that in many instances the cancers were accompanied by opportunistic infections, such as P. carinii pneumonia. The infections and cancers were later determined to be manifestations of AIDS. In addition to affecting homosexual men, the disease was detected in intravenous drug users, who became infected mainly by sharing contaminated hypodermic needles.
In 1983 French and American researchers isolated the causative agent, HIV. (In 2008 French virologists Françoise Barré-Sinoussi and Luc Montagnier were awarded the Nobel Prize for Physiology or Medicine for their discovery of HIV.) By 1985 serological tests to detect the virus had been developed.
Prevalence and distribution of HIV/AIDS
According to a 2011 United Nations report on AIDS, an estimated 34 million people were living with HIV, approximately 2.7 million people were newly infected with HIV, and about 1.8 million people died of AIDS and AIDS-related conditions in 2010. Between 1997 and 2010, the annual number of new infections dropped 21 percent, and since about 2005, the annual number of deaths from AIDS has also declined. The latter trend has been due in large part to improved access to treatment for the afflicted. Thus, there has been an increase in the overall number of people living with AIDS. Since 1981, however, more than 25 million people have died of the disease.
People living in sub-Saharan Africa account for about 70 percent of all infections, and in some countries of the region the prevalence of HIV infection of inhabitants exceeded 10 percent of the population. Rates of infection are lower in other parts of the world, but different subtypes of the virus have spread to Europe, India, South and Southeast Asia, Latin America, and the Caribbean. Rates of infection have levelled off somewhat in the United States and Europe. In the United States nearly one million people are living with HIV/AIDS, and half of all new infections are among African Americans. In Asia the sharpest increases in HIV infections are found in China, Indonesia, and Vietnam. Access to retroviral treatment for AIDS remains limited in some areas of the world, although more people are receiving treatment today than in the past.
The origin of HIV
Details of the origin of HIV remain unclear. However, a lent virus that is genetically similar to HIV has been found in chimpanzees and gorillas in western equatorial Africa. This virus is known as simian immunodeficiency virus (SIV), and it was once widely thought to be harmless in chimpanzees. However, in 2009 a team of researchers investigating chimpanzee populations in Africa found that SIV in fact causes AIDS-like illness in the animals. SIV-infected chimpanzees have a death rate that is 10 to 16 times higher than their uninfected counterparts. The practice of hunting, butchering, and eating the meat of chimpanzees may have allowed transmission of the virus to humans, probably in the late 19th or early 20th century. The strain of SIV found in gorillas is known as SIVgor, and it is distinct from the strain found in chimpanzees. Because primates are suspected to be the source of HIV, AIDS is considered a zoonosis , an infection that is shared by humans and other vertebrate animals.
Genetic studies of a pandemic strain of HIV, known as HIV-1 group M, have indicated that the virus emerged between 1884 and 1924 in central and western Africa. Researchers estimate that this strain of the virus began spreading throughout these areas in the late 1950s. Later, in the mid-1960s, an evolved strain called HIV-1 group M subtype B spread from Africa to Haiti. In Haiti this subtype acquired unique characteristics, presumably through the process of genetic recombination. Sometime between 1969 and 1972, the virus migrated from Haiti to the United States. The virus spread within the United States for about a decade before it was discovered in the early 1980s. The worldwide spread of HIV-1 was likely facilitated by several factors, including increasing urbanization and long-distance travel in Africa, international travel, changing sexual mores, and intravenous drug use.
Groups and subtypes of HIV
Genetic studies have led to a general classification system for HIV that is primarily based on the degree of similarity in viral gene sequence. The two major classes of HIV are HIV-1 and HIV-2. HIV-1 is divided into three groups, known as group M (main group), group O (outlier group), and group N (new group). Worldwide, HIV-1 group M causes the majority of HIV infections, and it is further subdivided into subtypes A through K, which differ in expression of viral genes, virulence, and mechanisms of transmission. In addition, some subtypes combine with one another to create recombinant subtypes. HIV-1 group M subtype B is the virus that spread from Africa to Haiti and eventually to the United States. Pandemic forms of subtype B are found in North and South America, Europe, Japan, and Australia. Subtypes A, C, and D are found in sub-Saharan Africa, although subtypes A and C are also found in Asia and some other parts of the world. Most other subtypes of group M are generally located in specific regions of Africa, South America, or Central America.
In 2009 a new strain of HIV-1 was discovered in a woman from Cameroon. The virus was closely related to a strain of SIV found in wild gorillas. Researchers placed the new virus into its own group, HIV-1 group P, because it was unique from all other types of HIV-1. It was unclear whether the newly identified virus causes disease in humans.
HIV-2 is divided into groups A through E, with subtypes A and B being the most relevant to human infection. HIV-2, which is found primarily in western Africa, can cause AIDS, but it does so more slowly than HIV-1. There is some evidence that HIV-2 may have arisen from a form of SIV that infects African green monkeys.
HIV is transmitted by the direct transfer of bodily fluids, such as blood and blood products, semen and other genital secretions, or breast milk, from an infected person to an uninfected person. The primary means of transmission worldwide is sexual contact with an infected individual. HIV frequently is spread among intravenous drug users who share needles or syringes. Prior to the development of screening procedures and heat-treating techniques that destroy HIV in blood products, transmission also occurred through contaminated blood products; many people with haemophilia contracted HIV in that way. Today the risk of contracting HIV from a blood transfusion is extremely small. In rare cases transmission to health care workers may occur by an accidental stick with a needle used to obtain blood from an infected person.
The virus can be transmitted across the placenta or through the breast milk from mother to infant; administration of antiretroviral medications to both the mother and the infant around the time of birth reduces the chance that the child will be infected with HIV. Antiretroviral therapy can reduce the risk of transmission from infected persons to their uninfected sexual partners by some 96 percent when prescribed immediately upon diagnosis.
HIV is not spread by coughing, sneezing, or casual contact (e.g., shaking hands). HIV is fragile and cannot survive long outside of the body. Therefore, direct transfer of bodily fluids is required for transmission. Other sexually transmitted diseases, such as syphilis, genital herpes, gonorrhoea, and Chlamydia, increase the risk of contracting HIV through sexual contact, probably through the genital lesions that they cause.
Life cycle of HIV
The main cellular target of HIV is a special class of white blood cells critical to the immune system known as helper T lymphocytes, or helper T cells. Helper T cells are also called CD4+ T cells because they have on their surfaces a protein called CD4. Helper T cells play a central role in normal immune responses by producing factors that activate virtually all the other immune system cells. These include B lymphocytes, which produce antibodies needed to fight infection; cytotoxic T lymphocytes, which kill cells infected with a virus; and macrophages and other effector cells, which attack invading pathogens. AIDS results from the loss of most of the helper T cells in the body.
HIV is a retrovirus, one of a unique family of viruses that consist of genetic material in the form of RNA (instead of DNA) surrounded by a lipoprotein envelope. HIV cannot replicate on its own and instead relies on the mechanisms of the host cell to produce new viral particles. HIV infects helper T cells by means of a protein embedded in its envelope called gp120. The gp120 protein binds to a molecule called CD4 on the surface of the helper T cell, an event that initiates a complex set of reactions that allow the HIV genetic information into the cell.
Entry of HIV into the host cell also requires the participation of a set of cell surface proteins that normally serve as receptors for chemokines (hormone like mediators that attract immune system cells to particular sites in the body). These receptors, which occur on T cells, are often described as coreceptors , since they work in tandem with CD4 to permit HIV entry into the cells. Chemokine receptors that are known to act as HIV coreceptors include CCR5 (chemokine [C-C motif] receptor 5) and CXCR4 (chemokine [C-X-C motif] receptor 4), both of which are classified as G protein-coupled receptors. The binding of gp120 to CD4 exposes a region of gp120 that interacts with the chemokine receptors. This interaction triggers a conformational change that exposes a region of the viral envelope protein gp41, which inserts itself into the membrane of the host cell so that it bridges the viral envelope and the cell membrane. An additional conformational change in gp41 pulls these two membranes together, allowing fusion to occur. After fusion the viral genetic information can enter the host cell. Both CCR5 and CXCR4 have generated significant interest as targets for drug development; agents that bind to and block these receptors could inhibit HIV entry into cells.
Once the virus has infected a T cell, HIV copies its RNA into a double-stranded DNA copy by means of the viral enzyme reverse transcriptase; this process is called reverse transcription because it violates the usual way in which genetic information is transcribed. Because reverse transcriptase lacks the “proofreading” function that most DNA synthesizing enzymes have, many mutations arise as the virus replicates, further hindering the ability of the immune system to combat the virus. These mutations allow the virus to evolve very rapidly, approximately one million times faster than the human genome evolves. This rapid evolution allows the virus to escape from antiviral immune responses and antiretroviral drugs. The next step in the virus life cycle is the integration of the viral genome into the host cell DNA. Integration occurs at essentially any accessible site in the host genome and results in the permanent acquisition of viral genes by the host cell. Under appropriate conditions these genes are transcribed into viral RNA molecules. Some viral RNA molecules are incorporated into new virus particles, while others are used as messenger RNA for the production of new viral proteins. Viral proteins assemble at the plasma membrane together with the genomic viral RNA to form a virus particle that buds from the surface of the infected cell, taking with it some of the host cell membrane that serves as the viral envelope. Embedded in this envelope are the gp120/gp41 complexes that allow attachment of the helper T cells in the next round of infection. Most infected cells die quickly (in about one day). The number of helper T cells that are lost through direct infection or other mechanisms exceeds the number of new cells produced by the immune system, eventually resulting in a decline in the number of helper T cells. Physicians follow the course of the disease by determining the number of helper T cells (CD4+ cells) in the blood. This measurement, called the CD4 count, provides a good indication of the status of the immune system. Physicians also measure the amount of virus in the bloodstream—i.e., the viral load—which provides an indication of how fast the virus is replicating and destroying helper T cells.
The genome of HIV mutates at a very high rate, and thus the virus in each infected individual is slightly different. The genetic mechanisms that underlie this individual variation have been investigated through approaches based on genome sequencing. The HIV-1 genome in 2009 was the first HIV genome to be sequenced in its entirety. Prior to this achievement, the ability of HIV RNA to fold into highly intricate structures had complicated attempts to elucidate the genomic sequence, and scientists could sequence only small segments of the genome. The HIV-1 genome is composed of 9,173 nucleotides of RNA (nucleotides are the building blocks of nucleic acids).
Sequencing revealed that variation occurs throughout the HIV genome but is especially pronounced in the gene encoding the gp120 protein. By constantly changing the structure of its predominant surface protein, the virus can avoid recognition by antibodies produced by the immune system. Sequencing also has provided useful insight into genetic factors that influence viral activity. Knowledge of these factors is expected to contribute to the development of new drugs for the treatment of AIDS.
Course of infection
The course of HIV infection involves three stages: primary HIV infection, the asymptomatic phase, and AIDS. During the first stage the transmitted HIV replicates rapidly, and some persons may experience an acute flulike illness that usually persists for one to two weeks. During this time a variety of symptoms may occur, such as fever, enlarged lymph nodes, sore throat, muscle and joint pain, rash, and malaise. Standard HIV tests, which measure antibodies to the virus, are initially negative because HIV antibodies generally do not reach detectable levels in the blood until a few weeks after the onset of the acute illness. As the immune response to the virus develops, the level of HIV in the blood decreases.
The second phase of HIV infection, the asymptomatic period, lasts an average of 10 years. During this period the virus continues to replicate, and there is a slow decrease in the CD4 count (the number of helper T cells). When the CD4 count falls to about 200 cells per micro litre of blood (in an uninfected adult it is typically about 1,000 cells per micro litre), patients begin to experience opportunistic infections—i.e., infections that arise only in individuals with a defective immune system. This is AIDS, the final stage of HIV infection. The most common opportunistic infections are Pneumocystis carinii pneumonia, tuberculosis, Mycobacterium avium infection, herpes simplex infection, bacterial pneumonia, toxoplasmosis, and cytomegalovirus infection. In addition, patients can develop dementia and certain cancers, including Kaposi sarcoma and lymphomas. Death ultimately results from the relentless attack of opportunistic pathogens or from the body’s inability to fight off malignancies.
A small proportion of individuals infected with HIV have survived longer than 10 years without developing AIDS. It was suspected for many years that such individuals mount a more vigorous immune response to the virus, but scientists could not explain why. Then, in 2006, a variation called a single nucleotide polymorphism, or SNP, in the HLA-G gene—human leukocyte antigen G, a gene that codes for a molecule that stimulates immune response—was identified in a subset of female prostitutes who had remained HIV-negative despite having had sexual contact with more than 500 HIV-positive men. In 2007 scientists identified three additional SNPs responsible for an estimated 15 percent of the variability in viral load and disease progression between HIV-infected individuals. Two of these SNPs are located in genes that code for HLA-B and HLA-C, molecules that are similar to HLA-G in that they specialize in pathogen recognition and immune system activation. The third SNP is located in a gene called HCP5 (HLA complex P5), an inactive retrovirus first incorporated into the human genome millions of years ago that shares similarities in DNA sequence with HIV and is thought to interfere with viral replication.
In 2009 scientists discovered that HIV is capable of rapidly mutating to escape recognition by certain HLA immune molecules. In particular, researchers identified two forms of the HLA-B gene, known as HLA-B*51 and HLA-B*27, that produced immune molecules particularly susceptible to escape by HIV. The mutation of HIV to avoid these molecules is directly correlated to the frequency at which the HLA-B*51 and HLA-B*27 genes occur within populations. For example, the percentage of HIV-infected individuals that carried mutant virus capable of escaping immune detection by HLA-B*51 and HLA-B*27 molecules was high in populations with the highest frequencies of the HLA-B*51 and HLA-B*27 genes. In contrast, in populations with the lowest frequencies of these genes, only a small percentage of HIV-infected individuals were infected with mutant virus. The ability of HIV to mutate and hence rapidly evolve to escape immune detection by the most prevalent HLA molecules is similar to the rapid adaptation and mutation of other infectious viruses such as influenza.
Diagnosis, treatment, and prevention
Tests and screening
Tests for the disease check for antibodies to HIV, which appear from four weeks to six months after exposure. The most common test for HIV is the enzyme-linked immunosorbent assay (ELISA). If the result is positive, the test is repeated on the same blood sample. Another positive result is confirmed using a more specific test such as the Western blot. A problem with ELISA is that it produces false positive results in people who have been exposed to parasitic diseases such as malaria; this is particularly troublesome in Africa, where both AIDS and malaria are rampant.
Polymerase chain reaction (PCR) tests, which screen for viral RNA and therefore allow detection of the virus after very recent exposure, and Single Use Diagnostic Screening (SUDS) are other options. Because these tests are very expensive, they are often out of reach for the majority of the population at risk for the disease.
Pharmaceutical companies are developing new tests that are less expensive and that do not need refrigeration, allowing for greater testing of at-risk populations worldwide. One such test, the Ora Quick at-home test, a mouth-swab antibody-detection system that produces results within about 20 to 40 minutes, was approved for in-home use in the United States in 2012. The test was made available for over-the-counter purchase and was more than 99 percent accurate in the detection of HIV-negative persons and 92 percent accurate in the detection of HIV-positive individuals.
HIV infection is treated with three classes of antiretroviral medications. Protease inhibitors, which inhibit the action of an HIV enzyme called protease, include ritonavir, saquinivir, indinavir, amprenivir, nelfinavir, and lopinavir. Nucleoside reverse transcriptase (RT) inhibitors (e.g., abacavir [ABC], zidovudine [AZT], zalcitabine [ddC], didanosine [ddI], stavudine [d4T], and lamivudine [3TC]) and non-nucleoside RT inhibitors (e.g., efavirenz, delavirdine, and nevirapine) both inhibit the action of reverse transcriptase. Each drug has unique side effects, and, in addition, treatment with combinations of these drugs leads to additional side effects including a fat-redistribution condition called lipodystrophy.
Because HIV rapidly becomes resistant to any single antiretroviral drug, combination treatment is necessary for effective suppression of the virus. Highly active antiretroviral therapy (HAART), a combination of three or four RT and protease inhibitors, has resulted in a marked drop in the mortality rate from HIV infection in the United States and other industrialized states since its introduction in 1996. Because of its high cost, HAART is generally not available in regions of the world hit hardest by AIDS. Although HAART does not appear to eradicate HIV, it reduces plasma viral load, thereby allowing the immune system to reconstitute itself. Levels of free virus in the blood become undetectable; however, the virus is still present in reservoirs, the best-known of which is a latent reservoir in a subset of helper T cells called resting memory T cells. The virus can persist in a latent state in these cells, which have a long life span due to their role in allowing the immune system to respond readily to previously encountered infections. These latently infected cells represent a major barrier to curing the infection.
Patients successfully treated with HAART no longer suffer from the AIDS-associated conditions mentioned above, although severe side effects may accompany the treatment. Patients must continue to take all of the drugs without missing doses in the prescribed combination, or they will risk developing a drug-resistant virus. In general, resistance develops because drug concentrations are too low, and while this can occur as a result of poor patient compliance, it also may occur as a result of drug interactions or poor absorption of drug by the body. If HAART is discontinued or fails, viral replication resumes, reflected in increased plasma viral load. This necessitates a change in the patient’s treatment regimen. Resistance testing is used to determine which individual drugs and classes of drugs have been rendered ineffective by viral resistance, thereby allowing health care providers to tailor the new HAART regimen, which is known as a salvage regimen, to the patient. Salvage regimens often entail multiple drug rescue therapy (MDRT), or mega-HAART, the use of between 5 and 9 different drugs, including RT and protease inhibitors and sometimes hydroxyurea.
Antiretroviral therapy may be either immediate or delayed. In the past, delayed antiretroviral therapy was the preferred approach, with treatment initiated once CD4 levels had fallen to 200 cells per microlitre of blood, which generally coincides with the establishment of symptomatic disease. In most patients, initiating treatment at this point provides maximal therapeutic effectiveness, in that it minimizes the severity of drug toxicities and thus the risk for discontinuance of treatment and development of drug resistance. However, studies have indicated that in patients with morbidity-increasing factors, such as coinfection with a hepatitis virus or unusually rapid CD4 decline or high viral load, initiating treatment earlier, when CD4 levels have declined to 350 cells per microlitre, can improve survival and delay the onset of AIDS-related diseases significantly. Other studies have indicated that beginning antiretroviral treatment in infants immediately following diagnosis, rather than waiting until symptoms appear, can reduce infant mortality and disease progression dramatically. Taken together with the ability of antiretroviral therapy to reduce the risk of disease transmission, such studies have resulted in treatment recommendations that are more dynamic today than in the past, thereby improving treatment outcomes for certain subsets of patients with HIV.
There is no cure for HIV infection. Efforts at prevention have focused primarily on changes in sexual behaviour such as the practice of abstinence and the use of condoms. Attempts to reduce intravenous drug use and to discourage the sharing of needles led to a reduction in infection rates in some areas.
Antiretroviral therapy represents another important prevention strategy. Research has indicated that preexposure prophylaxis (PrEP), in which uninfected persons take an antiretroviral pill daily, can be highly effective in preventing infection. PrEP studies conducted in Kenya, Uganda, and Botswana, for example, revealed that the Truvada pill, which contains the antiretroviral medications tenofovir and emtricitabine, reduced the risk of HIV infection by between 63 and 73 percent in sexually active individuals. Other study participants took a pill known as Viread, which contained only tenofovir; those individuals experienced 62 percent fewer infections relative to participants who did not take the pill. Truvada had been approved in 2004 by the U.S. Food and Drug Administration (FDA) as a combination therapy (used with other drugs) for HIV infection; in 2012, following further clinical investigation of its effectiveness for PrEP, it became the first drug to be approved by the FDA specifically for use in the prevention of HIV transmission.
The first vaccine to demonstrate some level of effectiveness in preventing HIV infection was RV144, which actually consisted of two different vaccines given in succession, a strategy known as “prime boost.” Each vaccine was designed to work against strains of HIV circulating in Southeast Asia. In 2009 results from a clinical trial involving more than 16,000 volunteers in Thailand revealed that RV144 reduced the risk of HIV infection by 31.2 percent in healthy men and women between the ages of 18 and 30. Subsequent analysis of the trial’s data, however, indicated that the reduction in risk was closer to 26 percent, too low for statistical significance (i.e., the chances for protection with vaccination were no better than the chances for protection in the absence of vaccination).
In 2010 scientists reported the discovery of naturally occurring antibodies that neutralize (inactivate) about 90 percent of HIV strains and hence have considerable potential for facilitating the generation of vaccines for HIV prevention. The antibodies neutralize virus particles through interactions with highly conserved CD4 receptors, which are similar or identical to each other and which are found on most strains of HIV. Knowledge of the mechanisms underlying the interaction between the antibodies and the CD4 receptors was being used for investigation into the development of synthetic molecules that mimic the antibodies and stimulate their production.
Vaginal antimicrobial gels also have been investigated for the prevention of HIV infection. These agents are particularly valuable for women in relationships where mutual monogamy or condom use have failed or are not possible. Some of the first gels tested in large trials included Ushercell, which was made up of cellulose sulfate, and PRO 2000, which contained a polymer of naphthalene sulfonate. Each of these gels was designed to prevent the binding of HIV to cells in the vagina. Although initial investigations were promising, both gels failed to demonstrate effectiveness when tested in large numbers of women (more than 1,400 women in the Ushercell trial and nearly 9,400 in the PRO 2000 trial). In 2010 scientists reported that a newer vaginal gel, formulated to contain 1 percent tenofovir, demonstrated success in early trials. The study involved 889 women in KwaZulu-Natal, South Africa, and indicated that, on average, the gel reduced the risk of HIV infection in women by 39 percent. Women who used the gel regularly experienced a 54 percent reduction in risk.
The identification of gene variations in HLA-B, HLA-C, HLA-G, and HCP5 has opened avenues of drug and vaccine development that had not been previously explored for HIV infection. Scientists anticipate that therapies aimed at these genes will serve as ways to boost immune response.