Abstract
Cytotoxic CD4+ T cells (CD4+ CTLs) limit HIV pathogenesis, as evidenced in elite controllers (a subset of individuals who suppress the virus without the need for therapy). CD4+ CTLs have also been shown to kill HIV-infected macrophages. However, little is known about their contribution towards HIV persistence, how they are affected following exposure to immune modulators like morphine, and what factors maintain their frequencies and function. Further, the lack of robust markers to identify CD4+ CTLs in various animal models limits understanding of their role in HIV pathogenesis. We utilized various PBMC samples obtained from SIV infected and cART treated rhesus macaques exposed to morphine or saline and subjected to flow cytometry evaluations. Thereafter, we compared and correlated the expression of CD4+ CTL-specific markers to viral load and viral reservoir estimations in total CD4+ T cells. We found that CD29 could be reliably used as a marker to identify CD4+ CTLs in rhesus macaques since CD29hi CD4+ T cells secrete higher cytotoxic and proinflammatory cytokines following PMA/ionomycin or gag stimulation. In addition, this immune cell subset was depleted during untreated SIV infection. Strikingly, we also observed that early initiation of cART reconstitutes depleted CD29hi CD4+ T cells and restores their function. Furthermore, we noted that morphine exposure reduced the secretion of proinflammatory cytokines/cytotoxic molecules in CD29hi CD4+ T cells. Lastly, increased functionality of CD29hi CD4+ T cells as depicted by elevated levels of either IL-21 or granzyme B hi T Bet+ gag specific responses were linked to limiting the size of the replication-competent reservoir during cART treatment. Collectively, our data suggest that CD4+ CTLs are crucial in limiting SIV pathogenesis and persistence.
Highlights
The proposed excision of latently infected HIV cells in a second person with HIV infection offers renewed optimism towards a cure that would usher an end to the AIDS crisis [1, 2]
Similar trends were observed with absolute CD29hi CD4+ T cells (Supplementary Figure 2A) and absolute CD4+ T cells (Supplementary Figure 2B), while absolute CD8+ T cells were elevated during Simian Immunodeficiency Virus (SIV) progression (Supplementary Figure 2C)
NK cell subset analysis revealed that there was a reduction in % CD16+CD56- NK cells, (P = 0.024) (Figure 1K) together with concurrent expansions of %CD16-CD56+ NK cells, (P = 0.039) (Figure 1L) and %CD16-CD56- NK cells (P = 0.039) that are later maintained during chronic infection (Figure 1M)
Summary
The proposed excision of latently infected HIV cells in a second person with HIV infection offers renewed optimism towards a cure that would usher an end to the AIDS crisis [1, 2]. HIV-infected individuals worldwide live different lifestyles stemming from varied cultural and sexual practices, co-exposures to other pathogens, and comorbid substance abuse not limited to the illicit use of drugs like morphine, cocaine, and heroin [6,7,8,9,10,11] These behaviors differentially impact the body’s immune response, alter disease pathogenesis and need to be considered during the development of a universal HIV cure [6, 12]. CD4+ T cells are highly plastic and exist as numerous phenotypes like T helper (Th) 1, Th 2, and Th 17, cytotoxic (CD4+ CTL), T follicular helper (Tfh), and T regulatory (T regs) [19] These diverse CD4+ T cell phenotypes express different transcriptional profiles during health and disease, have distinct fates, and carry various functions, including immune regulation (CD+ T regs) [20]. It was suggested that CD4+ CTLs were crucial in healthy aging, where they were found to be expanded while offering long-lasting protection [21]
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