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Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS). An epidemic that affects 50 million individuals worldwide, with 25-40% infected in Southern African countries.
Normally, the immune system produces T-lymphocytes to attack viruses and bacteria. HIV destroys the T-lymphocytes causing failure of the immune system exposing the body to opportunistic life-threatening infections without the ability to fight. Infection may occur by transfer via blood, semen, breast milk and vaginal fluids. HIV may be present within the infected immune cells or as free virus particles. Transmission occurs by: - unprotected sex with an infected person, contaminated needles, transmission from an infected mother to her baby at birth or by breast milk. (Harris, R., 2008) There are two types of HIV -HIV-1 and HIV-2, HIV-1 being pre-dominant. They appear to cause clinically indistinguishable AIDS, although it is seen that HIV-2 is not transmitted easily and period between initial infection and illness is longer in HIV-2.( Sharp, P. M. and B. H. Hahn ., 2010)
Untreated HIV develops to AIDS at a rate affected by viral, host and environmental factors. HIV primarily infects CD4+ T cells and antigen presenting cells. HIV reduces the level of CD4+ cells pre-dominantly in the gastro-intestinal tract, either by direct killing, increasing apoptosis or killing infected CD4+ T cells by CD8+ cytotoxic T lymphocytes.( Brenchley JM, et al ., 2004) Below a certain level of CD4+ T cell numbers, cell-mediated immunity is lost. When more CD4+ T cells are generated in response to HIV, the virus, making it a destructive cycle, infects more cells. AIDS is diagnosed when the level of CD4+ T cells decline below a certain level. (5ââ‚¬"80 cells per ÂÂµl of blood)(Milush, J. M., et al, 2007)
Since 1997, the existence of latent reservoir for HIV has been recognized. It is possible to recover HIV from resting CD4+ T cells even after 5 years of suppression of HIV-RNA levels. The virus particles number reduces during latency due to strong immune defence. However, the virus perseveres elsewhere, such as lymph nodes and virus replicates with follicular dendritic cells and macrophages. This may be due to the property of HIV to down regulate major histocompatibility complex class I responses allowing activated cells to relapse into a resting state, which contain integrated HIV in the genome, having the potential for further replication.( Dahl, V., et al , 2010)
HIV: A LATENT VIRUS
HIV is a large, spherical virus containing two copies of positive single stranded RNA encoding nine genes. The pathophysiology of HIV infection determines the effect of virus on the immune system. (Turner, B. G. and M. F. Summers, 1999)
After entering the body, the first stage of HIV infection is the primary infection during which stage, a large amount of HIV circulates in blood and CD8+ T lymphocytes are produced by the immune system in a process called seroconversion before which if HIV testing is done, a positive result is not guaranteed. The next stage is the asymptomatic stage where although not dormant, the level of HIV drops in the blood for an average of ten years and does not show any symptoms of HIV infection although HIV antibodies are detectable in blood which can be measures by the viral load test. The immune system is eroded by the HIV infection over time due to mutation of HIV making it more pathogenic leading to more deterioration. This is the symptomatic stage of infection as the body fails to keep up with the destruction of T lymphocytes, which leads to invasion by opportunistic pathogens, and cancers that could normally be prevented by the immune system. The final stage is the conversion of HIV to AIDS (Baliga, C. S., et al, 2008).
A latent reservoir of HIV, which is a small number of resting CD4+ T cells which persists with a higher stability than the main pool of HIV. These cells escape and host immune mechanisms because of very low levels of HIV messenger RNA. (Rong, L. and A. S. Perelson 2009).
In HIV infection, gp 120, the external glycoprotein of HIV interacts with CD4 and CCR5 or CXCR4 (chemokine receptor/co-receptor) - which permit gp120 to uphold the conserved binding site in a cryptic confirmation. There are 2 receptors-CD4 and CXR4- used due to the occurrence of 3 biological variants of HIV (R5, R5X4, X4). The accessibility of co-receptor targeted viral inhibitor impels the natural history of HIV infection. (Lusso, P. 2006).
Two classes of HIV latency are pre-integral and post-integral viral latency. Pre-integral latency is trailed by fusion of HIV to resting cells and is characterized by incomplete reverse transcription of viral genome. As such, this form of latency is lost promptly and does not explain long-term persistence of HIV. It is categorized by incomplete reverse transcription of viral genome.
The labile nature of pre-integration latency is not as clinically relevant as post-integration latency, which is not as clear as pre-integration latency. Post-integration latency is founded during shut-off of T-cell activation. The establishment of post-integration latency in memory cells to have cells imply direct infection of T-cells in memory CD4- T cells. ( Williams, S. A. and W. C. Greene., 2007).
Immune stimuli can activate distinctive population selectively resulting in HIV-1 activation from cellular compartments of latent reservoirs. T-lymphocytesââ‚¬â„¢ soluble products, pro-inflammatory cytokines, non-cytokine agents such as those belonging to phorbol ester family, soluble bacterial products may all be involved in activating HIV-1 expression from latently infected macrophages.( Broder, S., 2010)
In certain cases, there are HIV-positive patients who do not take AIDS drugs at all, yet remain healthy for more than one or two decades. The characteristics and immune responses of these people, termed Long Term Non-Progressors (LNTPs) provide insights into development of medication and treatment recommendations to other infected patients. The prevalence of LTNPs is independent of transmission, lifestyle co-factors, demographics, sexual behaviour although methodological concerns make comparisons difficult. Virology factors that differentiate LNTPs from progressive HIV infected patients include low levels of multiply spliced RNA and pro-viral RNA in blood and lower viral trapping in blood. (Dahl, V et al, 2010)
Studies on genetic factors revealed that a 32- base pair deletion in CCR5 gene provides resistance to HIV infection and delays progression of disease (Dean, M et al, 1996). The role of HLA antigens and transporter proteins in immune response suggested the association of genes in major histocompatibility in non-progression proved by the study that heterozygosity of HLA class I alleles is associated with disease progression in HIV. (Carrington, M., et al, 1999)
While genetic factors may explain a small portion of cases where individuals remain uninfected even with repeated, studies show that immune system may play a role in controlling HIV entry and replication with a wide range of immune responses to HIV-1 antigens. CD8+ T cells produce high levels of CC chemokine has and unstimulated CD8+ T cells prompts HIV-1 suppression infection (Furci, L., et al, 2002). Findings show that without treatment only 10% of non-progressors will continue remaining LNTPs and plasma viral levels will help us identify those patients. New developments on HIV research focuses on prevention of disease rather than infection and the studies on LNTP has and delayed progression of disease may provide important information on immune protection and curative strategies. (Dahl, V et al, 2010).
The cellular basis of HIV latency is gene silencing. Reactivation of latent viruses is a source of viral rebound. HIV, after reverse transcribing its RNA to DNA is integrated into host genome and transcribes the integrated genome using host machinery and is transmitted to daughter cells by mitosis which may not be transcriptionally active , leading to latently infected pool of cells. This kind of gene silencing was seen in actively dividing cells, which means it may not be an intrinsic property of the viral promoter system. Though higher gene density at the site of integration show higher level of gene expression, there are regions of the genome that are highly expressed, which are not favoured for integration maybe due to different rules governing the action of proviruses. Variegation- phenotypic differences in a population of clones is also observed in HIV infection. Higher levels of DNA methyltransferases is also observed after HIV infection.
In vivo studies are not as clear or ideal as in vitro studies since no protein markers are displayed by latent cells without disturbing their biological characteristics due to which selection is difficult. However, it can be theorized from molecular and cellular stability due to integration and resting CD4 T cells that dormant CD4 T cells are activated by virus generating latent cells that is the reason these cells are studied for understanding the pathology of latent cells.
The cells that are latently infected do not have a specific target for antiviral treatment or immunologic clearance due to which the virus attains refuge in these sites. An approach to achieve virus clearance is by therapeutically reactivating latent viruses followed by administration of antiviral drug although in vivo studies have been disappointing since they reside in sites that act as an immunologic sanctuary that cannot be penetrated by the anti-retroviral drug. (Mok, H. P. and A. Lever, 2008)
HIV uses anti-retro viral drugs as treatment for infection. When several medications are combined with therapies associated with a specific protease inhibitor, then it is called Highly Active Antiretroviral Therapy or HAART. High proportion of antiretroviral drug doses is required to maintain silencing of viral replication. The decreasing level of adherence leads to increase in failure rates. Studies show a more dynamic and empathic way for adherence without predicted the adherence before initiation and treatment, which is usually done in HAART. (Spire, B., et al, 2002)
The rate of HIV in recent years is higher in women than in men, especially women within childbearing years and vertical transmission is the most substantial risk factor for infants. At birth, clinical findings are unreliable in discriminating between infected and non-infected babies.
Antiretroviral therapy (ART) not only reduces viral load but also improves CD4+T cell counts. In situations of captivities, the rate of women infected with HIV is roughly double of the men infected HIV (Roberson, D. et al., 2009). The effect of ART includes gradual restoration of immune responses that are antigen specific. Though HAART reduces HIV-1 viremia to low levels, the viruses still persists in latent reservoirs and trace amounts in plasma. HAART has the ability to suppress on-going replication cycles and in vivo studies prove replication suppression. (Figure 2) Future research in HAART must aim at targeting latent reservoirs. (Shen, L. and R. F. Siliciano, 2008).
Figure 2: Action of HAART (Richman, D. D., et al, 2009)
The complexity of latent HIV-1 infection during HAART was made clear by validating that HIV-1 re-emergence upon sporadic cessation of HAART may not correspond to expression of resting CD4 lymphocytes. Monocytes and macrophages, which are important role players in HIV-1 pathogenesis does not induce cytopathic effects like T- lymphocytes during HIV-1 replication.
Structured therapy interruptions are a means of eliminating latently infected cells. In this method, HIV-specific immunity is enhanced by allowing periodic rebound and immune recognition. Other approaches such as ex vivo expansion of T-cell populations, use of colony stimulating factors or novel chemical agents are attempts to undermine immune recovery during HAART. Though these are not involved in targeting latent HIV-1 directly but they all aim to enhance immune responsiveness in individuals by latent cell elimination by HIV-1 expression re-activation. ( Butera, S. T., 2000)
Memory T-cells are well defined latent reservoirs of HIV, established when CD4 T-cells are activated by HIV that are infected, but are modified into terminally different memory T cells although other cells such as macrophages, haematopoietic stem cells may serve as reservoirs. Mechanism such as viral integration sites, chromatin modifications, and variations in transcription factors, miRNA interference, and DNA methyl transferase epigenetic control are all said to be involved in HIV latency. All these studies point towards the important fact that any long-term strategy for eliminating HIV must target HIV latency. As with any other diseases, if infection is detected earlier, better treatment options and preventive care can be made available. Imminent availability of safe and effective CCR-5 and CXCR-4 targeted presence in drug procedures will allow assessing the influence of blocking of virus entry on formation of latent HIV reservoirs, which may be the first step towards eradication of AIDS. The introduction of powerful anti-retroviral therapies since 1996 has increased the progression time between HIV infection and AIDS development. Hence, a lifelong treatment is required for HIV infection and this should involve eradication of the latent reservoir. There is no substantial evidence about the exact mechanism by which latency is achieved by HIV although there are many processes involved due to which targets for eliminating cells infected latently is still in its early stages and hence more research is required to explicate these areas.