OVERVIEW OF LATENT HIV/SIV RESERVOIR AND VIRAL REBOUND: DISSECTING THE IMPEDIMENTS TO FUNCTIONAL HIV CURE

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This section describes latent HIV and viral rebound; and how these important features of HIV/SIV pathogenesis affect the curing or eradication of the virus even with available potent antiretroviral therapy (ART). HIV is acronym for human immunodeficiency virus while SIV is acronym for simian immunodeficiency virus. HIV is unique because it has the ability to attack different cell types and tissues of the body; and the virus has a high mutational functionality that allows it to change its nature and become specifically resistant to antiretroviral agents. In the battle between the host immune response and the replication of HIV in vivo, HIV is always winning and having the upper arm because of its ability to establish a small repertoire of transcriptionally silent but replication competent provirus (latent HIV) in some selected cellular and anatomical sites of the body of people living with HIV/AIDS (PLHA) – so that the virus is always free and safe from immunological and pharmacological attacks emanating from the host and combined antiretroviral therapy (cART) respectively.

Latent HIV/SIV is defined as a replication competent but transcriptionally-silent HIV/SIV that persists in the body of an HIV infected individual for a long time and during the period of active ART, but also has the ability to resume replication upon the discontinuance or failure of ART. They do not replicate or produce viral proteins, and this prevents the efficient targeting of the virus in its sanctuaries or reservoir sites by potent ARTs and the infected host’s immunological response machinery. Because latent HIV are secluded and given protection by these reservoir cells, tissues or organs so that ART or host immunological response will not reach them, it makes it very challenging for the current therapeutic discoveries of clinical medicine to cure or eradicate the infectious virus (i.e., latent HIV) even from HAART-treated HIV/SIV individuals. HAART is acronym for highly active antiretroviral therapy. When ART is interrupted, viral rebound of new HIV infection is bound to occur; and in developing countries where treatment and health care is still pitiable, the situation could worsen – with already infected people having rapid viraemia coupled with other co-morbidities associated with HIV infection.

Viral rebound is an occasional clinical episode in HIV-infected patients, and this condition usually occurs when HIV at their latent or quiescent stage resurfaces in vivo either in the presence or absence of ART. More so, a small population of HIV infected individual’s still experience disease progression, as well as HIV co-morbidities and virologic failure despite being on cART. Viral rebound is defined as a repeated viral load that is >50 copies/ml of blood. HIV/SIV rebound leads to increase in the plasma viral load of HIV infected individuals, and this could be seen clinically as ‘viral blips’ when the plasma viral load (PVL) of HIV/SIV is measured in blood plasma. Viral rebound generally occurs when a person on ART has persistent, detectable levels of HIV in the blood after a period of undetectable levels especially after passing through some stages or levels of antiretroviral therapy (ART). Some of the major causes of viral rebound include drug resistance, patients poor compliance to therapy and poor adherence to an HIV treatment regimen. However, previous and recent reports on HIV/SIV reservoir and latency have shown that persistent proviral infection in a small pool of cells in the body including memory CD4+ T cells, cerebrospinal fluid (CSF), lymphoid cells/tissues and the brain cells (astrocytes) provides a continuous and long-lived source of rebound viraemia which is the major reservoir of HIV infection in HIV infected individuals.

Nevertheless, the major fortress and setback to finding a ‘functional cure’for HIV is due largely to a group of long lasting latently infected memory CD4+ T cells that persist even in the face of ART; and the clonal expansion and proliferation of infected T-cells is also another factor to be seriously considered in looking at HIV persistence in infected individuals. Total cure for HIV infection in humans ‘may’ become possible if the current medical technologies and HIV therapy can be re-invented to effectively target and dislodge latent HIV from their fortresses in the body especially from reservoir sites harbouring latently infected CD4+ T cells. However, it is also important to fully characterize and determine the amount of latent HIV in some neglected or uncharacterized reservoir sites of latent HIV such as the adipose tissues for example. More so, the bioavailability and concentration of antiretroviral agents in these cellular and anatomical sites of the body of PLHA is important because adequate concentration of ART in vivo will help in not only inhibiting viral replication efficiently, but it will help to forestall the emergence and redistribution of drug resistant HIV strains or variants among human population.

More questions still remains to be answered in terms of the actual reservoir of HIV/SIV, and how clonally expanded cells impact the reservoir sites. It is known that clonally expanded cells containing intact infectious provirus can persist and produce infectious virus for many years in individuals on cART. But the fraction or number of the replication-competent reservoir cells or tissues that is composed of clonally expanded cells in SIV/HIV individuals is still yet to be determined or clarified. Unraveling this phenomenon will help in the development of novel cART that will be effective in targeting clonally expanded SIV/HIV infected cells in PLHA on ART. And this may pave way for the discovery of a functional cure or vaccine for the treatment of HIV infection.     

Further reading

Cary D.C and Peterlin B.M (2016). Targeting the latent reservoir to achieve functional HIV cure [version 1; referee: 3 approved]. F1000Research, 5(F1000 Faculty Rev):1009.

Miles B and Connick E (2016). TFH in HIV latency and as sources of replication competent virus. Trends in Microbiology, 24(5):338-344.

Couturier J and Lewis D.E (2018). HIV persistence in adipose tissue reservoirs. Current HIV/AIDS Reports, 15(1):60-71.

Hirsch M.S (2008). Initiating therapy: when to start, what to use. J Infect Dis, 197:S252-260.

Hughes M.D and Ribaudo H.R (2008). The search for data on when to start treatment for HIV infection. J Infect Dis, 197:1084-1086.

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