Abstract
The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to an HIV/SIV cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCFs) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of NK cells in macaque lymph nodes that expressed BCF-homing receptor CXCR5 and accumulated within BCFs during chronic SHIV infection. These CXCR5+ follicular NK cells exhibited an activated phenotype coupled with heightened effector functions and a unique transcriptome characterized by elevated expression of cytolytic mediators (e.g., perforin and granzymes, LAMP-1). CXCR5+ NK cells exhibited high expression of FcγRIIa and FcγRIIIa, suggesting a potential for elevated antibody-dependent effector functionality. Consistently, accumulation of CXCR5+ NK cells showed a strong inverse association with plasma viral load and the frequency of germinal center follicular Th cells that comprise a significant fraction of the viral reservoir. Moreover, CXCR5+ NK cells showed increased expression of transcripts associated with IL-12 and IL-15 signaling compared with the CXCR5– subset. Indeed, in vitro treatment with IL-12 and IL-15 enhanced the proliferation of CXCR5+ granzyme B+ NK cells. Our findings suggest that follicular homing NK cells might be important in immune control of chronic SHIV infection, and this may have important implications for HIV cure strategies.
Highlights
The persistence of HIV/SIV reservoirs under combined antiretroviral therapy (ART) remains an obstacle to achieving sustained viral control upon ART discontinuation [1, 2]
The proportion of NK cells was significantly lower in lymph nodes (LNs) (P = 0.01) relative to the blood compartment (Figure 1B), the fraction of NK cells expressing CXCR5 was significantly (P < 0.0001) higher (5-fold) in LNs compared with the blood compartment (Figure 1C)
We investigated the dynamics and functional properties of CXCR5-expressing NK cells having B cell follicles (BCFs) homing potential during chronic SHIV infection in rhesus macaques
Summary
The persistence of HIV/SIV reservoirs under combined antiretroviral therapy (ART) remains an obstacle to achieving sustained viral control upon ART discontinuation [1, 2]. HIV/SIV has been shown to readily spread to the B cell follicles (BCFs), where follicular Th cells (Tfh cells) are preferentially infected and serve as viral reservoirs under ART [3–11]. Our lab and others reported an aberrant accumulation of virus-infected Tfh cells in the lymph nodes (LNs) and rectal mucosa of SIV-infected rhesus macaques with high viral load [10, 12, 13]. HIV controllers who develop robust antiviral CD8 T cell responses, the virus appears to preferentially persist in these LN follicles [12–15]. The lymphoid tissue serves as the principal reservoir site of infected cells, and its BCF compartment harboring reservoirs represents a unique site where cytolytic cells such as CD8+ T cells and NK cells have limited access [14, 16]. There is a need to identify immune mechanisms capable of eliminating infected cells from these lymphoid structures
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