Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction

• Published in: Journal of virology Vol. 91; no. 23
• Main Authors: Brocca-Cofano, Egidio, Kuhrt, David, Siewe, Basile, Xu, Cuiling, Haret-Richter, George S., Craigo, Jodi, Labranche, Celia, Montefiori, David C., Landay, Alan, Apetrei, Cristian, Pandrea, Ivona
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2017
• Subjects: Animals; Antibodies, Neutralizing - blood; Antibodies, Viral - biosynthesis; Antibodies, Viral - blood; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - physiology; B-Lymphocytes, Regulatory - immunology; B-Lymphocytes, Regulatory - physiology; Cercopithecus aethiops; Disease Progression; Epitopes - chemistry; Epitopes - immunology; HIV Infections - virology; Humans; Immunity, Humoral; Immunologic Memory; Interleukin-10 - blood; Lymphocyte Count; Macaca nemestrina; Pathogenesis and Immunity; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - metabolism; Simian Immunodeficiency Virus - pathogenicity; T-Lymphocytes, Helper-Inducer - immunology; nonpathogenic infection; simian immunodeficiency virus; B cell; follicular T helper cells; immune activation; pathogenic infection; humoral immune response
• DOI: 10.1128/JVI.01051-17
• ISSN: 0022-538X; 1098-5514

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. IMPORTANCE 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 immunization strategies aimed at preventing HIV disease progression.