Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

Abstract

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8 + T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV-specific CD8 + T cells are just a small fraction of the total HIV-specific CD8 + T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8 + effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (T SCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccineinduced antiviral responses and T SCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8 + T SCM cells and higher levels of CD8 + T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of T SCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.

Immunotherapeutic Potential of T Memory Stem Cells

“…In addition, CD4 + T SCM is highly permissible for VSV-G-HIV-1 virus infection in vitro, and expresses relatively low levels of intracellular viral restriction factors, such as SAMHD1, Trim5alpha, and APOBEC3G. Moreover, these restriction factors can prevent HIV-1 from replicating in myeloid and dendritic cells (151)(152)(153). It was found that the CD4 + T SCM of untreated HIV-1 infected persons contained high levels of HIV-1 RNA, which all indicated the sensitivity of CD4 + T SCM cells to HIV-1.…”

“…Recent studies have found that vaccination of the subtype C prophylactic HIV-1 vaccine candidate can induce more T SCM and antiviral. Compared with MVA alone and placebo, it induces more peripheral CD8 + T SCM cells and a higher level of CD8 + T cellmediated inhibition of the replication of different HIV-1 branches can respond to acute HIV infection or effectively control the chronic replication of HIV (152). Recently, a crosssectional study of 20 cases of HIV-infected patients on treatment alone and 20 cases of ART has revealed a new subset of CD4 + T cells: follicular regulatory T cells (TFR).…”

Elevated Numbers of HIV-Specific Poly-Functional CD8+ T Cells With Stem Cell-Like and Follicular Homing Phenotypes in HIV-Exposed Seronegative Individuals

“…Others investigators have also observed that CD8 + T cells from HIV uninfected subjects mediate a one-log inhibition of HIV-1 replication through non-cytotoxic mechanisms ( 72 – 74 ). We too made similar observations in our laboratory and have therefore used ≥1.5 log 10 inhibition as the cut-off for defining positive VIA response in an earlier study where we assessed vaccine-induced VIA response ( 15 ). As anticipated, CD8 + T cell-mediated VIA activity was detected only in HESN women.…”

“…CD8 + T cells have been shown to be important for controlling virus replication even during suppressive ART (9). More recent studies have shown that HIV-specific CD8 + T cells with unique phenotypic characteristics, such as CXCR5 + CD8 + T cells and TSCM cells, are associated with natural control of HIV and Simian Immunodeficiency Virus (SIV) infection (10)(11)(12)(13)(14)(15). Contemporary vaccine strategies designed to elicit high frequencies of anti-viral CD8 + T cells have used pathogenic SHIV (16) and SIV challenges in rhesus macaques (17)(18)(19)(20)(21).…”

Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4+ T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression

“…The self-renewal capacity and longer survival period of T SCM cells gives them the opportunity to differentiate into effector T cells (13). Increased frequency of T SCM cells has also been reported in HIV-vaccinated individuals as well as elite controllers (EC) (14,15). While there is evidence to suggest that T SCM cells are essential for differentiation and enrichment of mature central effector (CE), effector memory (EM), and terminal effector (TE) cells in HIV-1 infected individuals (16)(17)(18), the possible role of these cells in HIV-2 infection has not been well explored.…”