hiv is a very long and complicated topic for me
so with the corse of time i have been collecting data about this topic which i will like to share
as i think may help the students --
Introduction and History
Widespread awareness of HIV disease began with a brief report in 1981, published in the Morbidity and Mortality Weekly Report, of a rare pneumonia caused by Pneumocystis carinii (now known as P jiroveci) as well as other unusual infections in 5 young homosexual men in Los angeles.
An infectious agent was postulated, and, in 1983, a novel human retrovirus was isolated as the putative etiologic agent. That virus was eventually named human immunodeficiency virus, or HIV.
HIV-1 and the less common HIV-2 belong to the family of retroviruses. HIV-1 contains a single-stranded RNA genome that is 9 kilobases in length and contains 9 genes that encode 15 different proteins.The major viral proteins (some of which contain >1 protein subunit) are classified as structural proteins (Gag, Pol, and Env), regulatory proteins (Tat and Rev), and accessory proteins (Vpu, Vpr, Vif, and Nef).
Three major classes of HIV-1 have emerged: M (main), N (new), and O (outlier). Among M group viruses, which account for >90% of HIV infections worldwide, there are 9 subtypes, called clades, designated by the letters A-D, F-H, J, and K, as well as many recombinant forms. Variation between one clade and another in the amino acid sequences of the envelope protein may exceed 30%. Clade B, the most common subtype in the Americas and Western Europe, differs considerably from those clades found in Asia and Africa, where the majority of HIV-infected individuals reside. Viral diversity is greatest in sub-Saharan Africa. To date, most HIV drug development has targeted clade B. As HIV treatment is extended into regions where non-B clades predominate, issues of differential drug response, drug mutation patterns, and reliability of viral testing (ie, viral loads and resistance testing) may emerge.Sequence diversity among various clades also needs to be considered in vaccine development, as most HIV-specific neutralizing antibodies and some cytotoxic T-lymphocyte (CTL) responses are type specific.
HIV infection of a host cell begins with the binding of the virus particle (virion) to the host cell. This process is initiated when the surface envelope protein (Env, which consists of 3 copies each of the 2 subunit proteins gp120 and gp41) engages its primary receptor, the CD4 molecule on the surface of the target cell.Initial binding to CD4 exposes another portion of the Env trimer, which then binds to a coreceptor, usually the chemokine receptor CXCR4 (in the case of T-cell-tropic, or syncytium-inducing strains of HIV) or the chemokine receptor CCR5 (in the case of macrophage-tropic, or nonsyncytium-inducing strains). This coreceptor binding causes the gp41 trimer portion of the envelope molecule to spring open and "harpoon" the lipid bilayer of the target cell membrane. The "hairpin" domains of gp41 then fold together to pull the virus and host cell membranes together, allowing fusion to occur.The viral contents, including copies of the viral genetic material and the Pol protein (reverse transcriptase, or RT) thus enter the cytoplasm of the host cell. Reverse transcription, that is, the copying of the viral genetic material from RNA into DNA can then occur.
The preintegration complex (PIC), composed of the copied DNA (cDNA) and a number of viral and host proteins, then enters the cell nucleus, where the viral enzyme integrase mediates the insertion of the viral cDNA into the host chromosomal DNA.The resulting integrated DNA virus (also called a provirus, to distinguish it from the virion form) may remain latent for hours to years before becoming active through transcription (copying of DNA into RNA).Transcription of the viral genome is under complex control of a number of proteins, including Tat and cellular DNA transcription factors.Transport of the transcribed viral RNA out of the nucleus also depends on a number of host and viral factors, including Rev. The transcribed viral RNA may be transported out of the nucleus in its full-length form to serve as genetic material for new virions, or it may be partially or fully spliced. The unspliced, partially spliced, and fully spliced versions of viral RNA direct the synthesis of different viral proteins by the cell ribosomes. New viral particles are assembled at the plasma membrane and incorporate Gag subunits, Pol, Nef, Env, Vpr, and viral genomic RNA.The HIV viral protease enzyme acts following virion assembly to cleave viral proteins into functional structural and enzymatic components. Gag then functions in the budding of mature virions from the plasma membrane.The Nef protein acts on the cellular environment to promote replication by inhibiting the host immunologic response to HIV and inhibiting death of infected cells by apoptosis.
Current HIV therapies inhibit the viral replication process at the binding and entry stage (fusion inhibitors), the reverse transcription stage (nucleoside and nonnucleoside reverse transcriptase inhibitors [NRTIs and NNRTIs, respectively]), or the protein cleavage stage (PIs). Inhibitors of coreceptor binding, integration, and maturation are in clinical trials.
Individuals infected with HIV show both cellular and humoral (antibody) immune responses to the virus, but these responses are unable to prevent the ultimate progression of disease in the great majority of infected individuals. Cellular responses are mediated by CTLs (CD8 cells) and helper T lymphocytes (CD4 cells). CTLs inhibit HIV replication both directly, by recognizing and killing infected cells, and indirectly, by producing soluble chemokine antiviral factors.
CTL-mediated killing of virally infected host cells occurs through direct contact, whereby the T-cell receptor on the surface of the CTL recognizes a fragment (epitope) of an HIV protein bound to a major histocompatibility complex (MHC) class I molecule on the surface of the infected host cell. After this interaction, the CTL releases enzymes that kill the infected cell. CTL responses directed against certain epitopes of the Gag protein have been associated with slower HIV disease progression than CTL responses against other epitopes.CTLs also exert effects through soluble factors such as RANTES, macrophage inflammatory protein (MIP)-1-alpha, and MIP-1-beta, which inhibit HIV from infecting new cells by blocking HIV coreceptors.
CD4 responses to HIV are important in viral control, and strong HIV-specific CD4 responses are associated with lower HIV viral loads. CD4 cells respond to HIV antigens presented in conjunction with MHC class II molecules on the surface of infected cells. The fact that HIV infects CD4 cells themselves is an evolutionary strategy with a number of consequences. Because productive HIV infection occurs in activated CD4 cells, infection and killing of CD4 cells that are responding to HIV infection itself may cause a selective decrease in the number of HIV-specific CD4 cells. (HIV can also exist in nonactivated CD4 cells in a preintegrated form, which can become integrated if activation occurs within a few days.
Additionally, as some of the activated, infected CD4 cells differentiate into resting memory CD4 cells, they may carry copies of the HIV genome in a postintegrated form that can persist for decades. Current antiretroviral medications cannot efficiently eliminate the virus from cells in the resting state, leading to persistence of infection even in the presence of suppressive therapy.
Moreover, HIV continues to evolve under the selection pressure of the immune response that occurs in each infected individual, and mutations in the viral epitopes recognized by the immune system may enable the virus to escape the control of even broad and robust CD4 and CD8 HIV-specific responses.
Depletion of CD4 lymphocytes is the hallmark of HIV infection, and predicts an individual's risk for infection with opportunistic pathogens as well as other complications of HIV disease. Evidence has shown that both increased peripheral destruction and decreased production of CD4 cells likely play a role in this decline.
Humoral immunity appears to be less effective in controlling viremia than cellular responses, as HIV is remarkably effective at evading host antibody responses, and broadly neutralizing antibodies are rare.
The difficulty in eliciting broadly neutralizing antibody responses against HIV has posed a particularly difficult challenge to the development of a protective HIV vaccine.
The primary method of spread of HIV infection worldwide is through sexual exposure. In the United States and Europe, acquisition of the virus through homosexual contact remains important, and there is some evidence of increasing incidence of infection among young gay men and ethnic minorities.
MSM, however, now account for <50% of new infections in the United States.In the areas of highest HIV prevalence globally, heterosexual intercourse is the primary mode of transmission, accounting for approximately 70% of the overall sexual transmission.
HIV has been isolated from blood, seminal fluid, pre-ejaculate, vaginal secretions, cerebrospinal fluid, saliva, tears, and breast milk of infected individuals.
HIV-1 DNA sequences have also been detected in pre-ejaculatory fluid.
In genital fluids, HIV may be found in both cell-free and cell-associated compartments, but it is unknown which is responsible for productive infection.
Viral concentrations in tears and saliva are comparatively low, and there are substances in saliva that appear to inhibit infectivity. No cases of HIV infection have been documented to arise from contact with nonbloody saliva or tears.
Transmission of HIV occurs more frequently through penile-anal intercourse and penile-vaginal intercourse than through fellatio, although clear cases of transmission through oral sex exist.
Female-to-female HIV transmission has been reported, but is rare. In a meta-analysis, the overall efficacy of condoms in reducing HIV transmission was 69%.
Sexual activity that is associated with exposure to infected blood increases the risk of transmission, as does the presence of genital ulcers.
Serum HIV viral load is strongly associated with heterosexual transmission between HIV-serodiscordant African sexual partners, where transmission was noted to be rare at viral loads <1,500 copies/mL.
The effect of viral load reduction with ART on HIV transmission is being investigated. Intervention with antiretroviral medications soon after high-risk sexual exposures has been proven to be safe and may be effective in preventing transmission of HIV
Nonsexual HIV transmission can occur through transfusion with contaminated blood products, injection drug use, occupational exposure, or accidental needlesticks. The risk from occupational needlesticks to health care workers from known HIV-positive source patients in case series performed prior to the availability of potent ART was found to be 0.33-0.5%.
Factors increasing the risk of HIV acquisition from an occupational needlestick include deep injury, injury with a visibly bloody device, or injury with a device that had been previously used in the source patient's vein or artery.
Postexposure prophylaxis (PEP) has been associated with a reduction of HIV transmission after occupational needlestick events of approximately 80%.
HIV transmission through transfusion of contaminated blood products was recognized early in the epidemic.
With current testing methods, the risk of acquiring HIV from a unit of transfused blood in the United States is 1 in 676,000,
but is significantly higher in many developing countries.
In the absence of interventions, mother-to-child transmission occurs in approximately 25% of live births to HIV-infected mothers.
Various regimens of antiretrovirals can reduce the rate of perinatal transmission by 50% or more. Breast-feeding is also a risk factor for HIV transmission. Approximately one-third of cases of mother-to-child transmission result from breast-feeding, and the risk increases with the duration of breast-feeding.Thus, interventions to prevent mother-to-child transmission at delivery may be largely negated if mothers are not provided with safe alternatives to breast-feeding.
Primary HIV infection is defined as the time period from initial infection with HIV to the development of an antibody response detectable by standard tests. Data from careful prospective evaluations of populations at risk for HIV infection demonstrate that up to 87% of individuals who acquire HIV may experience some symptoms of primary HIV infection.
The acute viral syndrome of primary HIV infection (sometimes referred to as "seroconversion illness") was first defined in 1985, with symptoms resembling those of mononucleosis appearing within days to weeks following exposure to HIV.
Symptoms may be mild or severe and may last from a few days to several weeks, with the average duration being 14 days. The most common presenting symptom is fever, seen in over 75% of patients.
Other commonly reported symptoms include fatigue, lymphadenopathy, headache, and rash. The rash, which is present in 40-80% of cases, may be evanescent, is typically maculopapular in character, and typically involves the trunk.(Evaluation of cohorts from Kenya
and India found more frequent reports of joint pains, night sweats, and mucosal candidiasis and less frequent rash and pharyngitis in these study populations. A more severe clinical syndrome in primary HIV infection has been associated with a more rapid subsequent clinical course of HIV disease.
The nonspecific symptoms of primary HIV infection may make diagnosis a challenge. In a study of high-risk individuals presenting with symptoms consistent with primary HIV infection, only 25% were diagnosed during their initial presentation.
Diagnosis of HIV during the acute seroconversion phase requires not only high clinical suspicion but also an understanding of appropriate testing strategies. Routine HIV antibody testing may be negative for several weeks or even months after exposure in the so-called "window period."
During primary infection with HIV, plasma viral load often reaches very high levels in the range of millions of RNA copies/mL
Thus, for individuals in whom primary HIV infection is clinically suspected, HIV RNA assays, which have a sensitivity approaching 100% and specificity of 97.4% in this setting, should be included in the diagnostic evaluationIV RNA tests are not licensed for the diagnosis of HIV infection, and positive RNA tests during acute infection should be confirmed by documentation of subsequent HIV antibody conversion. The high levels of viremia seen in primary infection do not persist, however,(providing evidence of a host immune response capable of bringing the infection under some degree of control, at least in the short term.
During primary HIV infection, HIV-specific CD8 cells undergo a marked clonal expansion and express high levels of activation markers such as CD38 and human leukocyte antigen (HLA)-DR.
The breadth and strength of this CTL response correlate positively with the degree of viral control and inversely with the rapidity of clinical progression.
CD4 counts and CD4 function may decline during primary HIV infection, occasionally to levels that allow OIs to develop.Absolute CD4 count often rebounds after the primary infection, but may not return to a normal baseline. In patients with clinical progression of HIV disease, CD4 responses against HIV itself appear to remain particularly impaired following primary infection.
After the initial reduction of viremia, a viral "set-point" is established in each infected individual. The magnitude of this set-point correlates with the rate of progression of HIV disease
Studies of individuals during primary HIV infection have raised the question of whether the set-point might be reduced by early treatment.
Although early antiretroviral therapy may prserve immune function,
rapid control of viremia may also inhibit the full development of a mature immunologic response.
Carefully supervised interruptions of antiretroviral treatment after initial control during acute infection may permit the development of an effective immune response in the short term, but long-term follow-up suggests that increases in viral load and emergence of drug resistance may occur in such patients. The best strategy for treatment of acute HIV infection remains a matter of investigation.
Chronic HIV Infection
After the period of acute HIV infection--during which CD4 counts and viral load change dramatically--a relative equilibrium between viral replication and the host immune response is reached, and individuals may have little or no clinical manifestations of HIV infection. This time between initial infection and the development of AIDS may be long, averaging 10 years, even in the absence of treatment.
Despite the relative clinical latency of this stage of HIV infection, viral replication and CD4 cell turnover remain active, with millions of CD4 cells and billions of virions produced and destroyed each day.
During this period, most infected individuals will have progressive loss of CD4 lymphocytes and perturbation of immune function.
On average, CD4 counts will drop by 50-90 cells/無 per year in asymptomatic individuals, usually with an acceleration of this rate over time.
The rate of progression of infection may vary considerably. In adults, progression from infection to clinical AIDS is rare in the first 2 years of infection; however, reports describe rapid disease progression in infants infected by blood transfusion.
In a well-characterized cohort of HIV seroconverters who were identified in a retrospective analysis of stored serum samples from hepatitis B vaccine trials in the 1970s, 87% of infected individuals had developed AIDS by 17 years postseroconversion. Twelve percent maintained a CD4 count >500 cells/無 at 10 years, but only 3% maintained a CD4 count >500 cells/無 at 16 years after seroconversion.
During chronic HIV infection, HIV RNA levels in plasma correlate with the rate of CD4 decline, with higher plasma viral loads predicting more rapid progression to AIDS and death.
An undetectable HIV RNA level in peripheral blood is associated with stable CD4 lymphocyte counts, and increases in HIV RNA correlate with more rapid rates of CD4 cell decline.
The analogy of a train on a track (attributed to John Coffin of Tufts University, circa 1996) has been helpful in illustrating the independent contributions of CD4 count and HIV viral load in an individual person. If the infected individual is imagined as being on that train traveling toward a clinical event--such as acquiring an OI or dying from AIDS--the CD4 count provides information on the distance of the train from that destination, whereas the viral load provides information on the speed of the train in reaching the destination
A number of host factors influence HIV disease progression. Individuals who acquire HIV at an older age tend to have more rapid disease progression and shorter survival times.
Variation in HIV coreceptor molecules, notably CCR5, influences both HIV susceptibility and disease progression. A mutant allele of CCR5 with a 32-base-pair deletion, CCR5-delta-32, is frequent in populations of European origin (10-15% of Caucasians are heterozygous, and 1% are homozygous), and encodes a nonfunctional truncated protein that is not transported to the cell surface. Homozygotes for the delta-32 allele exhibit a strong, although not complete, resistance to HIV infection, whereas heterozygotes display nearly normal rates of infection, but delayed progression to AIDS.
Genetic differences in HLA alleles have also been shown to influence HIV disease susceptibility
and disease progression.
The class I alleles B35 and Cw4 have been associated with accelerated progression of disease,
as has general HLA homozygosity.
Because HLA class I alleles determine which viral epitopes can be presented to CD8 cells, greater diversity of HLA (heterozygosity) in an individual may reflect greater options for effective cell-mediated immunity to HIV. Conversely, HLA B27 and B57 have been associated with long-term nonprogression of HIV disease.
In particular, HLA B5701 has been found to be highly overrepresented in long-term nonprogressors.
Behavioral or psychological host factors may also influence HIV disease progression. More rapid HIV disease progression has been reported with unprotected anal intercourse,smoking,
poor nutrition, and depression
; however, not all studies confirm these findings. Drug use might be expected to influence HIV disease progression, but studies of that question have produced mixed results.
Additionally, differences in disease course based on the route of HIV transmission have been difficult to prove.
HIV virions infect human cells by first binding to the CD4 receptor on the cell surface. This alone is not sufficient for the virus to enter the host cell; binding to an additional coreceptor is also required. Macrophage- or M-tropic viruses preferentially infect monocytes and macrophages, using the cell surface protein CCR5 (R5) as the preferred coreceptor to enter cells, and produce a nonsyncytium-inducing (NSI) phenotype in cell culture. Conversely, thymocyte- or T-tropic viruses preferentially infect T cells, use CXCR4 (X4) as the preferred coreceptor to enter cells, and produce a syncytium-inducing (SI) phenotype in cell culture.
Dual-tropic viruses, which may use either CCR5 or CXCR4 coreceptors, also exist. M-tropic viruses are frequently found in early HIV infection, and a switch to T-tropic strains in the course of disease is associated with rapid CD4 cell depletion.
The concept of viral "fitness" refers to the pathogenicity of certain strains of HIV. HIV replicative capacity (RC) has been studied as a component of viral fitness. RC is a measure of the ability of a given virus to replicate successfully in a given environment.
During the course of drug treatment, mutations arise in the HIV reverse transcriptase and protease enzymes that make the virus resistant to particular drugs, thus conferring a selective advantage to that subpopulation that arises from a resistant variant.
Several of these mutations have been shown to cause a reduction in RC in the absence of drug when compared to wild-type virus.
Further accumulation of mutations over time under drug selection pressure may increase the "fitness" of the drug-resistant variant by further increasing phenotypic resistance,
or by increasing RC of the resistant virus.
The role of viral fitness on individual disease progression is just beginning to be understood.
Other viral factors may be important as well. For example, faster rates of disease progression have been observed in Ugandan individuals infected with subtype D compared with subtype A isolates.
Additionally, rare individuals who are infected with variant HIV strains, particularly those with a defective nef gene product, may experience slower disease progression.
Coinfections
The development of OIs during HIV disease not only indicates the degree of immunosuppression, but may also influence disease progression itself. When stratified by CD4 counts, patients with prior histories of OIs have higher mortality rates than those without prior histories of OIs
Hepatitis C coinfection is common in HIV-infected patients, present in up to 40-50% of all patients in urban setting and in 90% of intravenous drug users.
HIV clearly leads to more rapid HCV disease progression; however, the effect of HCV infection on HIV progression is less clear. In a study of the Swiss HIV Cohort, HCV coinfection was associated with poorer CD4 responses to ART, development of new AIDS-defining events, and increased mortality ; however, other authors have not found these associations.
HIV infection is usually diagnosed by testing serum for antibodies to HIV using a commercially available enzyme-linked immunosorbent assay (ELISA or EIA). Because the ELISA test is not entirely specific, positive results are confirmed with a Western blot assay, which identifies antibodies to specific components of HIV
. The 2-step process may mean that a patient must wait for a week or more to receive test results.
ELISA is quite sensitive in chronic HIV infection (although decline in antibody responses have been reported in advanced AIDS), but because antibody production does not occur immediately upon infection, an infected individual may test ELISA negative during a "window period" that varies in length from a few weeks to a few months after infection, depending on the individual case and assay used. Despite negative antibody testing during this window period, an individual may have high viral load and be at high risk of transmitting infection.
Newer methodologies allow antibody testing on saliva and urine specimens, although positive results should be confirmed with serologic testing. Home testing methods are also available.
Rapid HIV serum testing, with results available in 3-30 minutes, has shown 99-100% sensitivity and specificity compared to ELISA when tested in clinical settings, including in resource-poor settings and in pooled specimens..
"Detuned" Antibody Testing
By decreasing the sensitivity of ELISA assays, relatively recent infection (in which antibodies are present in lower concentrations and bind to HIV less effectively) can be distinguished from established infection (in which antibodies reach stable levels and have been selected for more avid binding to HIV). Soon after infection (but after the window period) an individual will test positive on the standard ELISA, but negative on the less-sensitive ("detuned") test. After maturation of the antibody response, both tests will give a positive result. Such "sensitive/less sensitive" or detuned ELISA testing strategies can be used to identify individuals who are in the early months of HIV infection and can help to identify incident infections in epidemiologic studies.
The CD4 cell count in blood correlates with the risk of OIs in HIV disease, and is therefore a useful marker for HIV disease staging. CD4 count is the main criterion for clinical decision making in guidelines developed in the United States for the prophylaxis of OIs and for HIV treatment.
The CDC recommends CD4 testing every 3-6 months in all HIV-infected persons, but different intervals may be appropriate to the individual case. More than 1.6 million CD4 cell measurements are performed annually by approximately 600 testing laboratories in the United States.
Because CD4 cells are a subset of all T lymphocytes, which are in turn a subset of all white blood cells, variations in CD4 count can occur in response to a variety of variables including concurrent infection, medications, stress, malnutrition, vitamin deficiencies, and normal diurnal variation. Often, these variables affect many subsets of lymphocytes and not exclusively CD4 cells; thus, the percentage of T lymphocytes that are CD4 positive will remain relatively stable. On the contrary, the depletion of T lymphocytes in HIV disease primarily affects CD4 cells, causing a relative CD4 cytopenia and a drop in the CD4 cell percentage. Additionally, an inversion of the normal CD4/CD8 cell ratio, which is usually >1 in non-HIV-infected individuals, may be seen with progressive CD4 cell depletion due to HIV. Thus, the CD4 percent and the CD4/CD8 ratio may help the clinician determine if a change in absolute CD4 count is due to the effects of HIV disease or to some other factor.
Until recently, most absolute CD4 cell counts were determined using 2 instruments, a hematology analyzer and a flow cytometer (dual-platform technology [DPT]). The CD4 count produced from DPT is the product of 3 laboratory measurements: the white blood cell count, the percentage of white blood cells that are lymphocytes (differential), and the percentage of lymphocytes that are CD positive (determined by flow cytometry). Single-platform technology (SPT) is designed to enable determinations of both absolute and percentage lymphocyte subset values using a single tube. SPT, introduced for clinical application in 1996 is becoming the preferred method of CD4 count determination in a number of laboratories.
Both SPT and DPT flow cytometry technology for CD4 count determination require specialized equipment and technician training. In resource-limited settings where CD4 count may be unavailable, the total lymphocyte count (TLC), which can be determined simply and cheaply, may be used as a surrogate for CD4 in determining stage of HIV infection. For example, in a cohort of HIV-positive people in south India, a TLC of <1,400 cells/無 has been shown to be a good predictor of a CD4 count <200 cells/無 and thus an appropriate surrogate marker for initiating cotrimoxazole prophylaxis.
TLC may also have applications in monitoring response to antiretroviral therapy in place of or in conjunction with CD4 count. In an analysis of patients initiating a triple antiretroviral drug regimen, an increase in TLC was associated with an increase in CD4 count and a decrease in plasma viral load.
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