Roles of CD8+ T cells and a regulatory T cells (TREG cells) as reservoir for latent HIV/SIV

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Role of CD8+ T cells

Apart from depleting the cellular levels of CD4+ T cells in vivo, HIV infection also leads to massive expansion of CD8+ T cells during viral replication; and the inability of the CD8+ T cell to reverse the pathogenesis of HIV using its antiviral prowess also contributes to the impairment of the infected host’s body to fighting and adequately controlling the infection. CD8+ T cells are known as cytotoxic T cells. They express the T cell receptor (TCR) marker, and CD8+ T cells are generated from the bone marrow like the CD4+ T cells. While CD4+ T cells recognize peptide molecules presented by major histocompatibility complex II (MHC II), CD8+ T cells only recognize peptide molecules presented by MHC I; and upon activation after recognizing intracellular parasites including viruses, CD8+ T cells becomes activated and thus direct pathogen destruction through the production of cytokines (such as tumor necrosis factor, TNF and interferons, IFN) and the secretion of granzymes and perforins.

CD8+ T cells are important mediators of the adaptive immune response; and they initiate their immunological attack through the killing of cancerous and virally infected cells. However, this important cellular component of adaptive immunity might be a potential target for HIV-1. CD8+ T cells are built and engineered to control HIV infection in vivo, but they ultimately fail to control viral replication and prevent the progression of the disease to AIDS even though a large amount of CD8+ T cells are usually secreted during the primary HIV infection stage. Why this notable viral killer (CD8+ T cell) is unable to kill the invading HIV and prevent its pathological consequences in the host is still unclear. There are some reports on the harborage and in vivo expression of HIV-1 by infected HIV-infected CD8+ T cells. HIV-1 Nef protein also protects infected primary cells against killing by cytotoxic T lymphocytes.

More so, the persistence of CD8+ T cell elevation in treated HIV-infected patients is associated with an increased risk of non-AIDS-related events. Also in another study, it was reported that there is an expansion of inefficient CD8+ T cells during acute HIV infection, and that the early CD4+ T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8dim T cell population – which is very less efficient in controlling HIV viraemia in vivo.However, an earlier report also opined that progression to AIDS is usually due to the late escape of the virus from an immunodominant cytotoxic T-lymphocyte response. The amount of infectious virus and/or provirus harboured by CD8+ T cells still remains unclear; and it is important to know this and define the genetic similarity or difference of this virus from the peripheral circulation in view of the focus on finding a functional cure and eradication strategy forHIV infection.

More so, it is still not certain whether HIV-infected CD8+ T cells contribute to the development of immunodeficiency in people living with HIV/AIDS (PLHA). And these necessitates the need for further investigation of the CD8+ T cells as a potential reservoir of latent HIV, and thus characterize the amount of provirus or infectious virus in this important cellular reservoir. The characterization of the access of CD8+ T cells into the germinal center (GC) and their ability to kill HIV-1 infected T-follicular helper (TFH) cells in the GC is not yet determined; and whether CD8+ T cells that infiltrate the GC of lymph node is defective or cidal enough to target and kill HIV-1 infected TFH still remains to be clarified. These are important research questions that need clarification in the search for a functional cure and vaccine for HIV infection globally.

Role of regulatory T cells (TREG cells)

Regulatory T cells (TREG) are a subpopulation of T cells that prevent the possible untoward effects of the immune system cells against self molecules by modulating the immune system to maintain immunological tolerance against self molecules. If the immune system fails to modulate and control itself against attacking self molecules, several clinical and immunological disorders can ensue and cause problem for the host. Autoimmune disorders or diseases are typical examples of a clinical condition that may arise when the immunosuppressive arm of the immune system fails to do its job properly. TREG cells are CD4(+)CD25(bright)CD62L(high) cells that actively down-regulate immune responses especially in the face of a pathogen invasion of a host body, such as that presented by HIV.

In another related study, TREG are referred to as a subset of CD4+CD25+FoxP3+ T cells capable of suppressing the activation, proliferation, and function of a wide variety of immune effector cells, including CD4+ and CD8+ T cells, natural killer (NK) and NKT cells, B cells, and antigen-presenting cells, such as dendritic cells and macrophages. TREG cells can be classified into thymic TREG cells (tTREG) and peripheral TREG cells (pTREG) based on their site of differentiation in the body after been developed from progenitor stem cells in the bone marrow. The role of TREG cells in HIV infection, pathogenesis and therapy is still not well understood. The excessive induction and proliferation of effector T cells could result in autoimmune disease; and thus it is the responsibility of the TREG cells to prevent this from happening.

TREG cells increases in population in vivo especially in the presence of a diseased state; and they also play major roles in HIV infection and its pathogenesis. TREG cells are potential target sites for HIV cure research; and the deficiency of TREG cells have also been linked to the development of autoimmune disorders and the inability of the immune system to control pathogen invasion of host cell. However, TREG cells can also be infected by HIV-1, and this ultimately increases the population of cells infected by the virus, thereby increasing the cellular reservoir sites of HIV-1 in vivo. In the cause of HIV invasion of host cells, TREG cells are believed to contribute in the suppression of the immune system (particularly the suppression of cell-mediated immune response) at an early stage of HIV/SIV infection, thus limiting target cells and reducing inflammatory reactions associated with the infection, but this simultaneously disrupts the clearance of HIV by the cell-mediated immune response and enhances the reservoir by pushing CD4+ T cells to a resting state – where it is unable to attack the virus.

This has made T regulatory (TREG) cells to be considered as both a beneficial and detrimental T cell subset population during acute HIV infection; and this is partly because TREG cells not only promote the generation of the latent HIV/SIV reservoir in vivo, but they also suppress the activity of CD8+ T cell responses that is supposed to mount a cytotoxic and cytolytic response against the invading viral pathogen. One study reported that the expression of TREG markers (particularly the FOXP3 marker) in CD4+ T cell population is a marker for disease severity after HIV infection, especially in progressive or chronic HIV infection. An understanding of the role of TREG cells in the pathogenesis of HIV as well as its role in the progression of the infection to AIDS stage is important because it will help to better direct any futuristic “functional cure” strategies for the disease due to the important role of TREG cells in modulating the immune system.

Further reading

Petrovas C, Mueller Y.M and Katsikis P.D (2004). HIV-specific CD8+ T cells: serial killers condemned to die? Curr HIV Res, 2(2):153-162.

Semenzato G, Agostini C, Chieco-Bianchi L and De Rossi A (1998). HIV load in highly purified CD8+ T cells retrieved from pulmonary and blood compartments. Journal of Leukocytes, 64:298-301.

Semenzato G, Agostini C, Ometto L, Zambello R, Trentin L, Chieco-Bianchi L and De Rossi A (1995). CD8+ T lymphocytes in the lung of acquired immunodeficiency syndrome patients harbor human immunodeficiency virus type 1. Blood, 85:2308-2314.

Collins K.L, Chen B.K, Kalams S.A, Walker B.D and Baltimore D (1998). HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature, 391:397–401.

Mercure L, Phaneuf D and Wainberg M.A (1993). Detection of unintegrated human immunodeficiency virus type 1 DNA in persistently infected CD8+ cells. J Gen Virol, 74:2077-2083.

Imamichi H and Lane H.C (2012). Regulatory T Cells in HIV-1 Infection: The Good, the Bad, and the Ugly. The Journal of Infectious Diseases, 205(10):1479–1482.

Eggena M.P, Barugahare B, Jones N, Okello M, Mutalya S, Kityo C, Mugyenyi P and Cao H (2005). Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol, 174(7):4407-4414.

Suvas S, Kumaraguru U, Pack C.D, Lee S and Rouse B.T (2003). CD4+CD25+ T cells regulate virus‐specific primary and memory CD8+ T cell responses. J Exp Med, 198:889-901.

Kleinman A.J, Sivanandham R, Pandrea I, Chougnet C.A and Apetrei C (2018). Regulatory T Cells As Potential Targets for HIV Cure Research. Frontiers in Immunology, 9:734.

Hazenberg M.D, Otto S.A, van Benthem B.H, Roos M.T, Coutinho R.A, Lange J.M, Hamann D, Prins M and Miedema F (2003). Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS, 17:1881-1888.

Sakaguchi S (2004). Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol, 22:531–562.

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