CLARIFICATION OF THE HIV PANDEMIC: RESERVOIR AND LATENCY

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HIV (Human Immunodeficiency Virus) is the causative agent of AIDS (acquired immunodeficiency syndrome). The virus is unique in its pathogenicity (i.e., its ability to cause disease) because HIV interferes with the body’s ability to fight the pathogens that cause diseases and infection in the body; and it does this by destroying the host’s immune system – so that its ability to fight off invading pathogens will be compromised and damaged. Over the past few years, more than a few fascinating papers addressing the issue of HIV reservoir and cure strategies targeted at finding a ‘functional cure’ for HIV infection has many publication and reviews – which have exhaustively (to our understanding) characterize or de-characterized some HIV reservoirs as primary or non-primary. However, the synthesis of HIV reservoirs by these many papers is still devoid of some other potential reservoir sites of HIV-1 such as the adipose tissue to mention a few. And irrespective of the many publications on HIV reservoir sites, only a handful of papers have tried to shed some light on the adipose tissue (AT) as one of the major sanctuaries on latent HIV that should be further investigated into, in order to fully understand the pathobiological role of AT in HIV pathogenesis as well as its role as a reservoir site.

Acquired immune deficiency syndrome (AIDS) is a pathological condition that is still without any ‘functional cure’, about three (3) decades since it terrified the human race. HIV and its other counterpart, SIV (simian immunodeficiency virus) which causes similar pathological conditions in some non-human primates (NHPs) is still without a functional cure or vaccine. And this has been largely attributed to some particular cells, tissues and organs in the body of HIV positive individuals that continually provide protection to latent HIV/SIV even in the presence of potent antiretroviral therapy (ART) that is supposed to suppress the replication of the virus in vivo. Till date, there is still no cure or vaccine for HIV/AIDS disease; and people living with HIV/AIDS (PLHA) all over the world still need to take antiretroviral therapy for a lifetime in order to keep the plasma viral load of HIV to below detectable limits (usually <50 copies/mL).

However, current antiretroviral therapy (cART) and/or highly active antiretroviral therapy (HAART) has the capacity to keep viral load of the infection at controllable levels even though these medications are still not without some unpleasant side effects. More worrisome is the fact that people living with HIV/AIDS (PLHA) have to take ART for a lifetime in order to avoid viral rebound of the infection especially when they take a break from medication. HIV reservoir cells, tissues or organs are specific cells and tissues of the body in which latent HIV are lucking and from which replication competent virus or provirus are usually released to cause new infections when HIV positive individuals are taken off therapy or off ART. One of the main challenges in the fight against HIV infection is to develop strategies that are able to eliminate the persistent viral reservoir that harbours integrated, replication-competent provirus within host cellular DNA. Latent HIV-1 or replication-competent provirus are protected from host immunological armamentarium and ART because they have found protection in some cellular and anatomical sites that are almost impenetrable by ART or the host’s immunological response.

Nevertheless, serious research is still ongoing to finding a “functional cure or vaccine” for HIV-1 infection, especially in purging these cellular and anatomical sites of the replication-competent provirus that continues to initiate new infection in PLHA even in the face of potent ART. Though latency is a common feature of the Retroviruses/Lentiviruses Family of viruses to which HIV belongs to, HIV latency in cellular and anatomical sites of PLHA is one of the major obstacle to curing and eradicating HIV infection; and this has contributed to the persistent and chronic infection experienced in PLHA from time to time even in the face of potent cART and when they are off ART. Latent HIV/SIV is a replication competent but transcriptionally-silent HIV/SIV that persists for a long time and even in the face of active cART. These viral strains also have the ability to resume replication upon the discontinuance or failure of ART; and thus initiate new infection in PLHA.

There are some notable reservoir sites and tissues, which have been researched into over the years since the discovery of HIV in the early 1980s. However, proper quantification of the actual amount of latent virus in these cellular and anatomical sites as well as elucidating and implementing novel strategies on how best to purge these HIV sanctuaries of the latent HIV-1 is still an ongoing research in many quarters; and we now wait and look to the future with hope that an HIV-1 cure or vaccine may be nearer than we thought. Typical examples of the notable HIV reservoir cells and tissues are CD4+ T cells, peripheral blood, macrophages, spleen, lymph nodes and mucosal surfaces of the gastrointestinal tract. However, there are still some other tissues and cells of the body that are yet to be fully investigated like the CD4+ T cells and macrophages – which are like the foundation from which data for finding a ‘functional cure or vaccine’ for the disease are currently emanating from.

Some tissues of the body especially adipose tissues, the brain cells, the gonads or reproductive cells (sperm cells and ova) and the mucosal surfaces of the gastrointestinal tract are not yet fully investigated like the CD4+ T cells, macrophages and lymph nodes to mention but a few. The degree of penetration and bioavailability of antiretroviral drugs in these cellular and anatomical compartments where latent HIV-1 is lurking is also another very serious issue that needs further clarification; and any “functional cure or vaccine” strategy/development must take ART penetration of reservoir sites seriously in order to get the maximum benefit of the approach. The two major features of the clinical episodes of individuals living with HIV/SIV in either humans or NHPs are currently (1) chronic inflammation and (2) HIV/SIV persistence in reservoir cells, tissues and organs even in the face of ART. These attributes are characteristics of adipose tissue and its accessory cells and tissues which are currently being considered as a ‘major’ reservoir of latent HIV/SIV, and this is due in part to its notable and vast immunological, pathological and pharmacological roles in microbial pathogenesis especially in HIV/SIV infection.

Adipose tissues (ATs) are loose connective tissues (with endocrine ability) that are composed mainly of adipocytes (fat cells or lipocytes) in addition to other accessory cells such as stromal vascular fraction (SVF) and adipose tissue macrophages. SVF and macrophages are immune system cells that play a role in inflammatory reaction or microbial pathogenesis; and this is also associated and seen in HIV-1 infection. Proper characterization of adipose tissue and its accessory cells in HIV/SIV infected individuals will help in elucidating the role and importance of this large organ (i.e., the adipose tissue) to the total reservoir of latent HIV; and thus contribute meaningful data towards finding a “functional cure or vaccine” for HIV infection.

However, several cure strategies including “shock and kill” and gene therapy are currently being investigated as putative approaches to “curing” HIV-1 infection in humans.

Further reading

Alexaki A, Liu Y and Wigdahi (2009). Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res, 6(5):388-400.

Burton G.F, Keele B.F, Estes J.D, Thacker T.C and Gartner S (2002). Follicular dendritic cell contributions to HIV pathogenesis. Semin Immunol, 14(4):275-284.

Crowe S.M and Sonza S.J(2000). HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. Leukoc Biol, 68(3):345-50.

Churchill M.J, Deeks S.G, Margolis D.M, Siliciano R.F and Swanstrom R (2016). HIV reservoirs: what, where and how to target them. Nat Rev Microbiol;14:55–60.

Koethe J.R, Hulgan T and Niswender K (2013). Adipose tissue and immune function: a review of evidence relevant to HIV infection. The Journal of Infectious Diseases, 208:1194-1201.

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