AIDS/HIV
Abstract
BACKGROUND. HIV-1 vaccine efforts are primarily directed towards eliciting neutralizing antibodies (nAbs). However, vaccine trials and mother to child natural history cohort investigations indicate that antibody-dependent cellular cytotoxicity (ADCC), not nAbs, correlate with prevention. The ADCC characteristics associated with lack of HIV-1 acquisition remain unclear. METHODS. Here we examine ADCC and nAb properties in pre-transmission plasma from HIV-1 exposed infants and from the corresponding transmitting and non-transmitting mothers’ breast milk and plasma. Breadth and potency (BP) is assessed against a panel of heterologous, non-maternal, variants. ADCC and neutralization sensitivity is estimated for the strains present in the infected mothers. RESULTS. Infants that eventually acquire HIV-1 and those that remain uninfected have similar pre-transmission ADCC BP. The viruses circulating in the transmitting and the non-transmitting mothers also have similar ADCC susceptibility. Infants with a combination of higher pre-transmission ADCC BP and exposure to more ADCC susceptible strains are less likely to acquire HIV-1. In contrast, higher pre-existing infant neutralization BP and greater maternal virus neutralization sensitivity does not associate with transmission. Infants have higher ADCC BP closer to birth and in the presence of high plasma IgG relative to IgA levels. Mothers with potent humoral responses against their autologous viruses harbor more ADCC sensitive strains. CONCLUSION. ADCC sensitivity of the exposure variants along with preexisting ADCC BP influence mother to child HIV-1 transmission during breastfeeding. Vaccination strategies that enhance ADCC responses are likely not sufficient to prevent HIV-1 transmission because strains present in chronically infected individuals can have low ADCC susceptibility. TRIAL REGISTRATION. NCT00164736 for BAN study
Authors
Allison S. Thomas, Carolyn Coote, Yvetane Moreau, John E. Isaac, Alexander C. Ewing, Athena P. Kourtis, Manish Sagar
Abstract
The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to HIV/simian immunodeficiency virus (SIV) cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCF) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of natural killer (NK) cells in macaque lymph nodes that expressed BCF-homing receptor C-X-C chemokine receptor 5 (CXCR5) and accumulated within BCF 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 helper T cells that comprises 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 to 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, which may have important implications for HIV cure strategies.
Authors
Sheikh Abdul Rahman, James Billinglsley, Ashish Arunkumar Sharma, Tiffany M. Styles, Sakthivel Govindaraj, Uma Shanmugasundaram, Hemalatha Babu, Susan Pereira Ribeiro, Syed A. Ali, Gregory K. Tharp, Chris Ibegbu, Stephen Waggoner, R. Paul Johnson, Rafick-Pierre Sékaly, Francois Villinger, Steven E. Bosinger, Rama Rao Amara, Vijayakumar Velu
Abstract
Duration of protection from SARS-CoV-2 infection in people with HIV (PWH) following vaccination is unclear. In a sub-study of the phase 2/3 the COV002 trial (NCT04400838), 54 HIV positive male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells >350 cells/ul) received two doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and MesoScale Discovery (MSD)), neutralisation, ACE-2 inhibition, gamma interferon ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that 6 months after vaccination the majority of measurable immune responses were greater than pre-vaccination baseline, but with evidence of a decline in both humoral and cell mediated immunity. There was, however, no significant difference compared to a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although were lower than wild type. Pre-existing cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater post-vaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the on-going policy to vaccinate PWH against SARS-CoV-2, and underpin the need for long-term monitoring of responses after vaccination.
Authors
Ane Ogbe, Matthew Pace, Mustapha Bittaye, Timothy Tipoe, Sandra Adele, Jasmini Alagaratnam, Parvinder K. Aley, M. Azim Ansari, Anna Bara, Samantha Broadhead, Anthony Brown, Helen Brown, Federica Cappuccini, Paola Cinardo, Wanwisa Dejnirattisai, Katie Ewer, Henry Fok, Pedro M. Folegatti, Jamie Fowler, Leila Godfrey, Anna L. Goodman, Bethany Jackson, Daniel Jenkin, Mathew Jones, Stephanie Longet, Rebecca A. Makinson, Natalie G. Marchevsky, Moncy Mathew, Andrea Mazzella, Yama F. Mujadidi, Lucia Parolini, Claire Petersen, Emma Plested, Katrina Pollock, Thurkka Rajeswaran, Maheshi N. Ramasamy, Sarah Rhead, Hannah Robinson, Nicola Robinson, Helen Sanders, Sonia Serrano Fandos, Tom Tipton, Anele Waters, Panagiota Zacharopoulou, Eleanor Barnes, Susanna Dunachie, Philip Goulder, Paul Klenerman, Gavin R. Screaton, Alan Winston, Adrian V.S. Hill, Sarah C. Gilbert, Miles Carroll, Andrew J. Pollard, Sarah Fidler, Julie Fox, Teresa Lambe, John Frater
Abstract
The duodenum is a major site of HIV persistence during suppressive antiretroviral therapy despite harboring abundant tissue-resident memory (Trm) CD8+ T cells. The role of duodenal Trm CD8+ T cells in viral control is still not well defined. We examined the spatial localization, phenotype, and function of CD8+ T cells in the human duodenal tissue from people living with HIV (PLHIV) and healthy controls. We found that Trm (CD69+CD103hi) cells were the predominant CD8+ T cell population in the duodenum. Immunofluorescence imaging of the duodenal tissue revealed that CD103+CD8+ T cells were localized in the intraepithelial region, while CD103–CD8+ T cells and CD4+ T cells were mostly localized in the lamina propria (LP). Furthermore, HIV-specific CD8+ T cells were enriched in the CD69+CD103–/lo population. However, the duodenal HIV-specific CD8+ Trm cells rarely expressed canonical molecules for potent cytolytic function (perforin and granzyme B) but were more polyfunctional than those from peripheral blood. Taken together, our results show that duodenal CD8+ Trm cells possess limited perforin-mediated cytolytic potential and are spatially separated from HIV-susceptible LP CD4+ T cells. This could contribute to HIV persistence in the duodenum and provides critical information for the design of cure therapies.
Authors
Leonard Mvaya, Trevor Khaba, Agness E. Lakudzala, Thandeka Nkosi, Ndaru Jambo, Innocent Kadwala, Anstead Kankwatira, Priyanka D. Patel, Melita A. Gordon, Tonney S. Nyirenda, Kondwani C. Jambo, Zaza M. Ndhlovu
Abstract
Type I interferons (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of antiretroviral therapy (ART)-treated HIV infection also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8 T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate pro-inflammatory plasma cytokines, expression of monocyte activation genes, IL-12 induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates (NHPs) treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrate that IFN-α blockade during ART-treated SIV infection is both safe and associated with the induction of immune/erythroid pathways that reduce viral persistence during ART while mitigating the weight loss and anemia that typically ensue following ART interruption.
Authors
Louise A. Swainson, Ashish Arunkumar Sharma, Khader Ghneim, Susan Pereira Ribeiro, Peter Wilkinson, Richard M. Dunham, Rebecca G. Albright, Samson Wong, Jacob D. Estes, Michael Piatak, Steven G. Deeks, Peter W. Hunt, Rafick-Pierre Sekaly, Joseph M. McCune
Abstract
Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7-35 days of ATI in 9/10 animals, with post-treatment control of viremia seen in 5/5 Mamu-A*01+ macaques. Single-genome sequencing revealed initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells prior to ATI. Thus, the GI tract may be an initial source of rebound virus but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides novel insight into the features of viral rebound in pediatric infection and highlights the application of a non-invasive technique to monitor areas of HIV-1 expression in children.
Authors
Veronica Obregon-Perko, Katherine M. Bricker, Gloria Mensah, Ferzan Uddin, Laura Rotolo, Daryll Vanover, Yesha Desai, Philip J. Santangelo, Sherrie Jean, Jennifer S. Wood, Fawn C. Connor-Stroud, Stephanie Ehnert, Stella J. Berendam, Shan Liang, Thomas H. Vanderford, Katharine J. Bar, George M. Shaw, Guido Silvestri, Amit Kumar, Genevieve G. Fouda, Sallie R. Permar, Ann Chahroudi
Abstract
Knowledge of immune activation in the brain during acute HIV infection is crucial for the prevention and treatment of HIV-associated neurological disorders. We determined regional brain (basal ganglia, thalamus, and frontal cortex) immune and virological profiles at 7 and 14 days post infection (dpi) with SIVmac239 in rhesus macaques. The basal ganglia and thalamus had detectable viruses earlier (7 dpi) than the frontal cortex (14 dpi) and contained higher quantities of viruses than the latter. Increased immune activation of astrocytes and significant infiltration of macrophages in the thalamus at 14 dpi coincided with elevated plasma viral load, and SIV colocalized only within macrophages. RNA signatures of proinflammatory responses, including IL-6, were detected at 7 dpi in microglia and interestingly, preceded reliable detection of virus in tissues and were maintained in the chronically infected macaques. Countering the proinflammatory response, the antiinflammatory response was not detected until increased TGF-β expression was found in perivascular macrophages at 14 dpi. But this response was not detected in chronic infection. Our data provide evidence that the interplay of acute proinflammatory and antiinflammatory responses in the brain likely contributed to the overt neuroinflammation, where the immune activation preceded reliable viral detection.
Authors
Raja Mohan Gopalakrishnan, Malika Aid, Noe B. Mercado, Caitlin Davis, Shaily Malik, Emma Geiger, Valerie Varner, Rhianna Jones, Steven E. Bosinger, Cesar Piedra-Mora, Amanda J. Martinot, Dan H. Barouch, R. Keith Reeves, C. Sabrina Tan
Abstract
HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4 T-cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on ART or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal ARV drugs revealed no differences in drug peneration between the duodemum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T-cell activation was inversely correlated with loss of gut CD4 T-cells in PLWH alone. T-cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4 T-cells is a key event in the HIV pathogensis of PLWH in South Africa, yet the underlying mechanisms remain unknown.
Authors
Osaretin E. Asowata, Alveera Singh, Abigail Ngoepe, Nicholas Herbert, Rabiah Fardoos, Kavidha Reddy, Yenzekile Zungu, Faith Nene, Ntombifuthi Mthabela, Dirhona Ramjit, Farina Karim, Katya Govender, Thumbi Ndung’u, J. Zachary Porterfield, John H. Adamson, Fusi G. Madela, Vukani T. Manzini, Frank Anderson, Alasdair Leslie, Henrik N. Kløverpris
Abstract
Natural aging and human immunodeficiency virus (HIV) infection are associated with chronic low-grade systemic inflammation, immune senescence, and impaired antibody (Ab) responses to vaccines such as influenza (flu). We investigated the role of Interleukin (IL)-21, a CD4 T follicular helper cells (Tfh) regulator, on flu vaccine Ab response in non-human primates (NHPs) in the context of age and controlled simian immunodeficiency virus (SIV) mac239 infection. Three doses of the flu vaccine with or without IL-21-IgFc were administered at 3-month intervals in aged SIV+ NHPs following virus suppression with anti-retroviral therapy. IL-21 treated animals demonstrated higher day 14 post-boost Ab responses which associated with expanded CD4+ T CM cells and peripheral (p) Tfh expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT), expanded activated memory B cells and contracted CD11b+ monocytes. Draining lymph node (LN) tissue from IL-21 treated animals revealed direct association between LN follicle Tfh density and frequency of circulating TIGIT+ pTfh cells. We conclude that IL-21 enhances flu vaccine-induced Ab responses in SIV+ aged RM acting as an adjuvant modulating LN germinal center activity. Strategies to supplement IL-21 in aging could be a valuable addition in the toolbox for improving vaccine responses in an aging HIV+ population.
Authors
Daniel Kvistad, Suresh Pallikkuth, Tirupataiah Sirupangi, Rajendra Pahwa, Alexander Kizhner, Constantinos Petrovas, Francois Villinger, Savita Pahwa
Abstract
We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEV) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 reduced in sEV from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti-miR-324-5p or anti-miR-186 induced consistent changes in Ltbp2, Wisp2, and Nebl expression. Knockdown of Ltbp2 (Latent-transforming growth factor beta-binding protein 2) downregulated markers of adipocyte differentiation (Fabp4, Pparg, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1β, IL6, and Ccl20). Our studies suggest a unique sEV miRNA signature related to dysregulation of Dicer in adipose in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.
Authors
Suman Srinivasa, Ruben Garcia-Martin, Martin Torriani, Kathleen V. Fitch, Anna R. Carlson, C. Ronald Kahn, Steven K. Grinspoon
No posts were found with this tag.
