SYNOPSIS OF CELLULAR HIV/SIV RESERVOIRS AND THEIR ROLE IN HIV LATENCY

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In this section, we highlight some notable HIV/SIV reservoirs that are cellular-bound, while also defining the term ‘viral reservoir site’. It must be noted that both cellular and anatomical reservoir sites of latent HIV helps the virus to persist for a very long time; and thus act as factories for not only the perpetuation of the infectious virus, but also as spring for the release of new virions or variants (different from the initial wild type virus, due to mutation and development of antiviral resistance) that have the ability to initiate newer, and in most cases a more virulent infectious process in people living with HIV/AIDS (PLHA). The cellular HIV/SIV reservoirs includes a group of special compartments or cells of the body (in this case, HIV infected hosts) to which HIV has immense specificity and propensity to cleave to upon invasion of a suitable host cell, and thus maintain a long lasting population of latent HIV/SIV even in the face of potent antiretroviral therapy (ART). These cells usually have receptors that mediate HIV attachment and final penetration of the host cell – which are both necessary prerequisites for the establishment of viral persistence, virulence and pathological conditions` in the infected individuals (PLHA). However, the most striking features of these reservoir cellular compartments of the individual living with HIV/SIV is that, they continue to serve as sources of new infection especially when HIV infected individuals are taken off therapy or off ART.

A viral reservoir site is defined as a cell type or anatomical site in the body of PLHA, where a replication-competent form of latent HIV/SIV can accumulate and persist stably. These HIV/SIV reservoir sites are usually maintained throughout the lifetime of PLHA even in the presence of ART and they continue to be a constant source of infectious virus that is both replicationally and transcriptionally competent to initiate new infection in the HIV infected individual. There are both tissue and cellular HIV reservoirs. The cellular HIV/SIV reservoirs are the reason why it is still impossible for HIV to be cured or eradicated by the combined antiretroviral therapy (cART); and this is largely due in part to the fact that they continue to maintain some population or amount of quiescent HIV/SIV that continue to replenish the general population with the infectious virus from time to time, and especially in the event of ART discontinuation. Thus, HIV positive individuals continue to take ART for a lifetime since there is still no cure for the disease. Typical examples of cellular HIV/SIV cellular reservoirs include CD4+ T cells, macrophages, astrocytes, monocytes and cells of the gonads.

Role of CD4+ T cells as reservoir for latent HIV/SIV

CD4+ T cells or T helper cells are a subpopulation of the lymphocytes and a vital immune system cells that plays a central role in immunological response to the invasion of a host body by a pathogen (bacteria, fungi or virus); and they induce B cells to proliferate and differentiate into specific antibody producing cells which attack the invading pathogen or antigen. They play a central role in regulating the immune system function; and CD4+ T cells also supplement cellular immune responses to pathogens either specifically or non-specifically. Other extended functions of the CD4+ T cells include induction of macrophages for increased microbial attack, recruitment of immune system cells such as the neutrophils to infection sites, recruitment of immune system cells to sites of inflammation and the stimulation of cytokine production.

There are several subpopulations of CD4+ T cells including T helper 1 (Th1), Th2, Th17, and induced regulatory T cells (iTreg cells); and these subpopulations of T cells are usually infected by HIV, owing in part to the fact that they possess the CD4 receptor – which is a unique and choice spot for HIV attachment. HIV mainly targets lymphoid CD4+ T cells; however HIV still can infect other cell types that express the CD4 marker including macrophages, dendritic cells and other non immune system cells. HIV/SIV enters the host cells using the CD4+ T cell receptor (TCR), CCR5 receptors and the CXCR4 receptors; and they are mainly responsible for mediating and promoting the attachment and entry of the virus into host cells prior to integration of their genome into the host own genome. A reduction in the levels of CD4+ T cell levels in peripheral blood of HIV infected individuals is indicative of an infection that may be leading to AIDS condition; and this shows that the virus is actively replicating after taking control of the host immune system machinery.

Current ART has the ability to keep HIV replication under control by suppressing the plasma viral load of the infection (<50 copies/ml) and thus reduce the viral load of the pathogen in the blood, but highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (cART) still cannot cure infected hosts of the infection. And this is majorly due to the hiding and perpetuation of latent HIV in certain cellular and anatomical sites of the body in PLHA, of which the CD4+ T cells is the number one reservoir and choice spot of the virus for hiding and dodging any immunological or pharmacological actions directed towards them. CD4+ T cells are the primary target of HIV/SIV during HIV infection; and they are massively depleted during chronic HIV infection, thus incapacitating the host’s ability to fight the invading virus. This predisposes the infected individual to several co-morbidities or opportunistic infections that ruins the health of the patient.The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4+ T-cell populations in close association with progressive impairment of cellular immunity and increasing susceptibility to opportunistic infections.

CD4+ T cells are the primary cellular reservoirs of HIV/SIV in HIV positive individuals (or PLHA); and this important component of the lymphocyte or T cells is the most widely studied cellular reservoir of latent HIV. CD4+ T cells are a major reservoir for the maintenance of latent HIV-1 proviral DNA; and they are the bane and the current nuisance to eradicating the virus from infected human host – since cART and the immune system of the HIV infected individual still cannot purge them from their hiding places in the host. The naïve and the memory CD4+ T cells are the two main populations of resting CD4+ T cells that are usually infected by HIV, and mostly prevalent in HIV positive individuals. Both the naïve and memory resting CD4+ T cells usually lack the chemokine receptor type 5 (CCR5 receptors) but they both have a high level expression of the chemokine receptor type 4 (CXCR4 receptor) – which is CD184 marker, a highly activated binding point for T-cell tropic HIV strains. Both CCR5 and CXCR4 are used as co-receptors by HIV/SIV to target, enter and infect specific immunologically-bound cells.

The memory CD4+ T cells have a long life span, expanding several years; and this cellular reservoir have the ability to reactivate and initiate viral persistence and infection in a host following the stoppage of ART. The CD4+ T cell count is perhaps one of the most important factors that are used for the clinical establishment of AIDS condition due to the depletion of this important arm of the immune system by HIV-1 upon host entry. However, some question still remains to be answered about this important component of the immune system, which is perhaps responsible for coordinating both the humoural and cell-mediated immune response. Most importantly is how CD4+ T cells dies in the face of HIV-1 infection. Most CD4+ T cells are not dying because of a toxic action of products encoded by HIV-1, but instead, CD4+ T cell death occurs as a consequence of a powerful defensive innate immune response launched by the host against the invading virus leading to a cellular form of suicide rather than virological murder.

Remarkably, the biological differences between CD4+ T cells in the peripheral circulation and the CD4+ T cells in secondary lymphoid tissues such as lymph nodes and spleen may also play important roles in HIV-1 pathogenesis. However, the exact mechanisms that spur chronic inflammatory reactions in PLHA especially the role of pyroptosis in the development of chronic inflammation observed during HIV infection on- or off-ART is still undetermined. Identifying the role of pyroptosis in HIV-1 pathogenesis will help to decipher and provide novel HIV-1 therapeutics that will help to target the reservoir sites since HIV-1 treatment is now moving towards functional cure” and “eradication”.

Role of follicular Helper T cells (TFH cells) as reservoir for latent HIV/SIV

TFH cells are subpopulations of the T cells that are found in the peripheral circulation and within the B cell follicles of secondary lymphoid organs that includes the spleen and lymph nodes. They help in the formation and maintenance of germinal centers (GCs) in B cell follicles after encountering antigens. TFH cells also migrate into GCs where they majorly help in the selection of B cells that produce potent plasma cells which go on to secrete specific and high-affinity antibodies that identify and stop the nefarious activities of antigens that invaded the host cell or body. Generally, TFH cells play a pivotal role in the generation of long-lived humoural immunity by providing help to B cells in the germinal centers (GCs), ensuring their differentiation to memory B cells and plasma cells; and their differentiation is in part regulated by chemical messengers such as cytokines – which are abundantly produced during HIV-1 infection to spur the inflammatory process associated with the disease.

GCs are sites within secondary lymphoid organs where B cells proliferate, differentiate, and mutate their antibody genes, and switch the class of their antibody [from a less potent antibody (IgM) to a high potent antibody (IgG)] during a normal immunological response to an infection. The selection and generation of memory B cells which generate a quick and specific immunological response upon the body’s second encounter with similar antigen in the future occurs in the GCs. In PLHA and who are either on cART or off-cART, TFH cells are hotspots for HIV persistence; and the preservation of latent HIV-1 in TFH cells may significantly contribute to the persistent and/or chronic infection seen in PLHA from time to time, especially when they are taken off therapy. A fundamental function of T helper cells (TH) is to provide “immunological help” to B cells and regulate their proliferation and immunoglobulin class switching, especially in the germinal-center (GC) structures. The peripheral T follicular helper cells are the major HIV reservoir within central memory CD4 T cells in peripheral blood from chronically HIV-infected individuals on cART.

Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. It is important to study further the immunological and protective role of the TFH cells in the face of HIV infection, in order to understand how they provide a sanctuary for latent HIV strains; and thus take into consideration their potential in contributing to the cellular reservoir of HIV in PLHA. TFH cells are vital for the development and maintenance of GC and host humoural immune responses during HIV/SIV infection, and TFH cells are important sources of replication competent HIV-1 during latency since they are one of the major reservoirs of the latent virus. However, there are still many outstanding questions regarding the role played by TFH cells in HIV-1 pathogenesis. Most importantly is how TFH cells could be infected by follicular dendritic cells (FDCs). Studies that target TFH cells in HIV-1 infection are needed, in order to determine the role of TFH and FDC during latency, so that HIV-1 cure strategiescan be properly suggested and developed. More so, it is still yet to be determined whether pre-TFH cells in the GC is a potential target of HIV-1 due to their high expression of CCR5 receptor sites; and it is still not clear how far TFH cells serve as a long-term reservoir for HIV-1 in the presence of optimal ART. These are potential research options for HIV/AIDS researchers to investigate, in order to contribute practicable research data geared towards discovering and developing a functional cure and vaccine for HIV infection.

Further reading

Schacker T (2008). The role of secondary lymphatic tissue in immune deficiency of HIV infection. AIDS, 22:S13–S18.

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of microorganisms. 12th edition. Pearson Benjamin Cummings Publishers. USA.

Brooks G.F., Butel J.S and Morse S.A (2010). Medical Microbiology, 23rd edition. McGraw Hill Publishers. USA.

Zhu J and Paul W.E (2008). CD4 T cells: fate, functions and faults. Blood, 112(5):1557-1569.

Zhu J, Yamane H and Paul W.E (2010). Differentiation of effector CD4 T cell populations. Annu Rev Immunol, 28:445–489.

Paul W.E and Seder R.A (1994). Lymphocyte responses and cytokines. Cell, 76:241–251.

Okoye A.A and Picker L.J (2013). CD4+ T cell depletion in HIV infection: mechanisms of immunologic failure. Immunol Rev, 254(1):54-64.

Schmitt N and Ueno H (2015). Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol, 34:130–136.

Chiodi F, Bekele Y, Graham R.L and Nasi A (2017). IL-7 and CD4 T follicular helper cells in HIV-1 infection. Front Immunol, 8:451.

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