Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction

Abstract

We compared and contrasted pathogenic (in pig-tailed macaques [PTMs]) and nonpathogenic (in African green monkeys [AGMs]) SIVsab infections to assess the significance of the B cell dysfunction observed in simian (SIV) and human immunodeficiency virus (HIV) infections. We report that the loss of B cells is specifically associated with the pathogenic SIV infection, while in the natural hosts, in which SIV is nonpathogenic, B cells rapidly increase in both lymph nodes (LNs) and intestine. SIV-associated B cell dysfunction associated with the pathogenic SIV infection is characterized by loss of naive B cells, loss of resting memory B cells due to their redistribution to the gut, increases of the activated B cells and circulating tissue-like memory B cells, and expansion of the B regulatory cells (Bregs). While circulating B cells are virtually restored to preinfection levels during the chronic pathogenic SIV infection, restoration is mainly due to an expansion of the "exhausted," virus-specific B cells, i.e., activated memory cells and tissue-like memory B cells. Despite of the B cell dysfunction, SIV-specific antibody (Ab) production was higher in the PTMs than in AGMs, with the caveat that rapid disease progression in PTMs was strongly associated with lack of anti-SIV Ab. Neutralization titers and the avidity and maturation of immune responses did not differ between pathogenic and nonpathogenic infections, with the exception of the conformational epitope recognition, which evolved from low to high conformations in the natural host. The patterns of humoral immune responses in the natural host are therefore more similar to those observed in HIV-infected subjects, suggesting that natural hosts may be more appropriate for modeling the immunization strategies aimed at preventing HIV disease progression. The numerous differences between the pathogenic and nonpathogenic infections with regard to dynamics of the memory B cell subsets point to their role in the pathogenesis of HIV/SIV infections and suggest that monitoring B cells may be a reliable approach for assessing disease progression. We report here that the HIV/SIV-associated B cell dysfunction (defined by loss of total and memory B cells, increased B regulatory cell [Breg] counts, and B cell activation and apoptosis) is specifically associated with pathogenic SIV infection and absent during the course of nonpathogenic SIV infection in natural nonhuman primate hosts. Alterations of the B cell population are not correlated with production of neutralizing antibodies, the levels of which are similar in the two species. Rapid progressive infections are associated with a severe impairment in SIV-specific antibody production. While we did not find major differences in avidity and maturation between the pathogenic and nonpathogenic SIV infections, we identified a major difference in conformational epitope recognition, with the nonpathogenic infection being characterized by an evolution from low to high conformations. B cell dysfunction should be considered in designing imm...

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

“…As pathogenic SIV infections are associated with B-cell dysfunction [76], we next assessed the fate of CD20 + B-cell populations during the earliest stages of SIVsab infection of AGMs,…”

Predominant envelope variable loop 2-specific and gp120-specific antibody-dependent cellular cytotoxicity antibody responses in acutely SIV-infected African green monkeys

“…Furthermore, vaccine-elicited antibody responses in the RV144 efficacy trial were mapped to both conformational and linear V2 epitopes, suggesting that V2-specific IgG responses with anti-viral activity may not only target linear V2 epitopes [ 9 , 14 ]. Interestingly, it has been shown that conformational epitope recognition of SIV Env-specific antibody responses differs greatly between nonpathogenic and pathogenic SIV infections in natural SIV hosts [ 23 ]. Thus, ADCC-mediating IgG responses in humans and AGMs may target both linear V2 and conformational gp120 epitopes within HIV and SIV Env.…”

“…SIV Env-specific IgG responses in chronically SIV-infected AGMs more frequently target gp120 epitopes compared to SIV-infected RMs [ 20 ]. While previous studies reported that B cell depletion in SIV-infected AGMs has no appreciable effect in disease progression outcome [ 22 ], it has also been shown that SIV-associated B cell dysfunction is associated with pathogenic SIV infection, and not in non-pathogenic SIV infection in natural SIV hosts [ 19 , 23 ]. Moreover, we previously demonstrated that SIV Env gp120-specific IgG monoclonal antibodies (mAbs) isolated from chronically SIV-infected AGMs mediated robust virus capture activity, and ADCC—an antibody function that has been associated with delayed progression to AIDS in RMs [ 20 , 24 ].…”

Pharmacokinetics and Immunological Effects of Romidepsin in Rhesus Macaques

“…Whole blood was stained to monitor the impact of RMD on the immune cell populations. TruCount was used to determine absolute counts of CD3 + , CD4 + , CD8 + T cells and CD20 + B cells as described (51)(52)(53). Fifty microliters of whole blood were stained with antibodies against CD3-V450, CD4-APC, CD20-APC-H7, and CD45-PerCP in TruCount tubes (BD Biosciences, Franklin Lakes, NJ, USA) with a set number of fluorescent beads as internal standards.…”