The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites.
Kan Luo, Hua-Xin Liao, Ruijun Zhang, David Easterhoff, Kevin Wiehe, Thaddeus C. Gurley, Lawrence C. Armand, Ashley A. Allen, Tarra A. Von Holle, Dawn J. Marshall, John F. Whitesides, Jamie Pritchett, Andrew Foulger, Giovanna Hernandez, Robert Parks, Krissey E. Lloyd, Christina Stolarchuk, Sheetal Sawant, Jessica Peel, Nicole L. Yates, Erika Dunford, Sabrina Arora, Amy Wang, Cindy M. Bowman, Laura L. Sutherland, Richard M. Scearce, Shi-Mao Xia, Mattia Bonsignori, Justin Pollara, R. Whitney Edwards, Sampa Santra, Norman L. Letvin, James Tartaglia, Donald Francis, Faruk Sinangil, Carter Lee, Jaranit Kaewkungwal, Sorachai Nitayaphan, Punnee Pitisuttithum, Supachai Rerks-ngarm, Nelson L. Michael, Jerome H. Kim, S. Munir Alam, Nathan A. Vandergrift, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Barton F. Haynes, M. Anthony Moody
The second-generation HIV-1 integrase strand transfer inhibitor (InSTI) dolutegravir (DTG) has had a major impact on the treatment of HIV-1 infection. Here we describe important but previously undetermined pharmacodynamic parameters for DTG. We show that the dose-response curve slope, which indicates cooperativity and is a major determinant of antiviral activity, is higher for DTG than for first-generation InSTIs. This steepness does not reflect inhibition of multiple steps in the HIV-1 life cycle, as is the case for allosteric integrase inhibitors and HIV-1 protease inhibitors. We also show that degree of independence, a metric of interaction favorability between antiretroviral drugs, is high for DTG and nucleoside reverse transcriptase inhibitors. Finally, we demonstrate poor selective advantage for HIV-1 bearing InSTI resistance mutations. Selective advantage, which incorporates both the magnitude of resistance conferred by a mutation and its fitness cost, explains the high genetic barrier to DTG resistance. Together, these parameters provide an explanation for the remarkable clinical success of DTG.
Sarah B. Laskey, Robert F. Siliciano
Early after HIV infection there is substantial depletion of CD4+ T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I–V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (Mx1, TNF-α), immune activation (Ki-67), and the CD4+ T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4+ T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4+ T cells after 96 weeks of cART.
Claire Deleage, Alexandra Schuetz, W. Gregory Alvord, Leslie Johnston, Xing-Pei Hao, David R. Morcock, Rungsun Rerknimitr, James L.K. Fletcher, Suwanna Puttamaswin, Nittaya Phanuphak, Robin Dewar, Joseph M. McCune, Irini Sereti, Merlin Robb, Jerome H. Kim, Timothy W. Schacker, Peter Hunt, Jeffrey D. Lifson, Jintanat Ananworanich, Jacob D. Estes, on behalf of the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4–binding site–sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs–specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.
Eric Meffre, Aaron Louie, Jason Bannock, Leo J.Y. Kim, Jason Ho, Cody C. Frear, Lela Kardava, Wei Wang, Clarisa M. Buckner, Yimeng Wang, Olivia R. Fankuchen, Kathleen R. Gittens, Tae-Wook Chun, Yuxing Li, Anthony S. Fauci, Susan Moir
Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4+ T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the
Eileen P. Scully, Ainsley Lockhart, Wilfredo Garcia-Beltran, Christine D. Palmer, Chelsey Musante, Eric Rosenberg, Todd M. Allen, J. Judy Chang, Ronald J. Bosch, Marcus Altfeld
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