Compartmentalization of Simian Immunodeficiency Virus Replication within Secondary Lymphoid Tissues of Rhesus Macaques Is Linked to Disease Stage and Inversely Related to Localization of Virus-Specific CTL

Abstract

We previously demonstrated that HIV replication is concentrated in lymph node B cell follicles during chronic infection and that HIV-specific CTL fail to accumulate in large numbers at those sites. It is unknown whether these observations can be generalized to other secondary lymphoid tissues, or whether virus compartmentalization occurs in the absence of CTL. We evaluated these questions in SIVmac239-infected rhesus macaques by quantifying SIV RNA+ cells and SIV-specific CTL in situ in spleen, lymph nodes and intestinal tissues obtained at several stages of infection. During chronic asymptomatic infection prior to simian AIDS (SAIDS), SIV-producing cells were more concentrated in follicular compared to extrafollicular regions of secondary lymphoid tissues. At day 14 of infection, when CTL have minimal impact on virus replication, there was no compartmentalization of SIV-producing cells. Virus compartmentalization was diminished in animals with SAIDS, which often have low frequency CTL responses. SIV-specific CTL were consistently more concentrated within extrafollicular regions of lymph node and spleen in chronically infected animals regardless of epitope specificity. Frequencies of SIV-specific CTL within follicular and extrafollicular compartments predicted SIV RNA+ cells within these compartments in a mixed model. Few SIV-specific CTL expressed the follicular homing molecule CXCR5 in the absence of the extrafollicular retention molecule CCR7, possibly accounting for the paucity of follicular CTL. These findings bolster the hypothesis that B cell follicles are immune privileged sites and suggest that strategies to augment CTL in B cell follicles could lead to improved viral control and possibly a functional cure for HIV infection.

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…Although it remains possible that other mechanisms, such as T cell exhaustion, may also play a role, our data are in line with other recent reports of IL-15-induced migration of memory T cells out of the peripheral blood into tissue. 18 It is well established that CD8 1 T cells are predominantly excluded from B-cell follicles, [1][2][3][4]19 and that during HIV and SIV infection, these lymph node follicles become sanctuary sites for viral replication by avoiding antiviral CD8 1 T cells. 5 In the absence of virus-specific CD8 1 T-cell surveillance, B-cell follicles are thus established as long-lasting sites of the HIV and SIV viral reservoir.…”

“…[1][2][3][4] Viral pathogens like HIV and Epstein-Barr virus exploit this anatomic segregation to establish persistent reservoirs in CD4 1 follicular helper T (T FH ) cells and B cells, respectively, residing within the B-cell follicle. In HIV elite controllers and antiretroviral therapy (ART)-treated patients, T FH cells are the major source of persistent HIV.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…In vitro, GC Tfh cells are more susceptible to infection with HIV‐1 than non‐GC Tfh cells or CXCR5 − extrafollicular CD4 + T cells,170, 171 and in vivo they have been shown to constitute the major CD4 T‐cell compartment for virus replication in both HIV‐1 172, 173 and SIV174, 175 infections. Furthermore, Tfh cell populations in both LNs and blood constitute a major (although not the only) site of SIV/HIV latency in macaques/humans receiving antiretroviral therapy 171, 176, 177, 178, 179.…”

“…GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183. Virus replication in GC Tfh cells may also be facilitated by the limited ability of antiviral CD8 + T cells to enter B‐cell follicles,168, 171, 175, 179, 184 although recent studies in the lymphocytic choriomeningitis virus (LCMV) mouse model show that persisting virus can be cleared from Tfh cells and B cells by a CXCR5 +  CD8 + T‐cell population that is able to enter B‐cell follicles,185, 186, 187 raising the intriguing prospect that if an analogous antiviral CD8 + T‐cell population expressing sufficiently high levels of CXCR5 could be induced in humans, this may enable targeting of Tfh cells that harbor persistent HIV‐1 such as the latent pool.…”

Splenic Damage during SIV Infection

“…In addition, red pulp macrophages constitute a source of prolonged viral production, as infected macrophages are not effectively killed by cytotoxic T lymphocytes. Even though SIV-specific cytotoxic T lymphocytes are numerous within the red pulp, 88 they do not efficiently promote macrophage death. 89 In addition to contributing to SIV infection in the spleen, macrophages are immune to the cytopathic effects of HIV/SIV and may represent a source of latent virus.…”