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Limited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH).We measured SARS-CoV-2-specific humoral and cellular responses in people with and without HIV recovering from COVID-19 ( n = 39 and n = 43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing postacute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T-cell responses, as well as differences in the prevalence of PASC.Among PWH, we found broadly similar SARS-CoV-2-specific antibody and T-cell responses as compared with a well matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2-specific memory CD8 + T cells ( P = 0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2-specific CD4 + T cells ( P = 0.007). Higher CD4 + /CD8 + ratio was associated with lower PD-1 expression on SARS-CoV-2-specific CD8 + T cells (0.34-fold effect, P = 0.02). HIV status was strongly associated with PASC (odds ratio 4.01, P = 0.008), and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms.We identified potentially important differences in SARS-CoV-2-specific CD4 + and CD8 + T cells in PWH and HIV-negative participants that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.

BackgroundLimited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH).MethodsWe measured SARS-CoV-2 specific humoral and cellular responses in people with and without HIV recovering from COVID-19 (n=39 and n=43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing post-acute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T cell responses, as well as differences in the prevalence of PASC.ResultsAmong PWH, we found broadly similar SARS-CoV-2-specific antibody and T cell responses as compared with a well-matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2 specific memory CD8+ T cells (p=0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2 specific CD4+ T cells (p=0.007). Higher CD4/CD8 ratio was associated with lower PD-1 expression on SARS-CoV-2 specific CD8+ T cells (0.34-fold effect, p=0.02). HIV status was strongly associated with PASC (odds ratio 4.01, p=0.008), and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms.ConclusionsWe identified potentially important differences in SARS-CoV-2 specific CD4+ and CD8+ T cells in PWH and HIV-negative participants that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.

Background There is mounting evidence for the presence of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), but there is limited information on the spectrum, magnitude, duration, and patterns of these sequelae as well as their influence on quality of life. Methods We assembled a cohort of adults with a documented history of SARS-CoV-2 RNA positivity at ≥2 weeks past onset of coronavirus disease 2019 (COVID-19) symptoms or, if asymptomatic, first positive test. At 4-month intervals, we queried physical and mental health symptoms and quality of life. Results Of the first 179 participants enrolled, 10 were asymptomatic during the acute phase of SARS-CoV-2 infection, 125 were symptomatic but not hospitalized, and 44 were symptomatic and hospitalized. During the postacute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping, and anosmia/dysgeusia were most common through 8 months of observation. Symptoms were typically at least somewhat bothersome and sometimes exhibited a waxing-and-waning course. Some participants experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with performance of usual activities. The median visual analogue scale rating of general health was lower at 4 and 8 months compared with pre-COVID-19. Two clusters of symptom domains were identified. Conclusions Many participants report bothersome symptoms following onset of COVID-19 with variable patterns of persistence and impact on quality of life. The substantial variability suggests the existence of multiple subphenotypes of PASC. A rigorous approach to the prospective measurement of symptoms and functional manifestations sets the stage for the next phase of research focusing on the pathophysiologic causes of the various subgroups of PASC.

Background The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown. Methods We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods. Results During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio [95% confidence interval {CI}, 1.01–1.28]; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio [95% CI, 1.01–1.62]; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio [95% CI, .98–1.70]; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio [95% CI, 1.11–1.86]; P Conclusions Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158 in reducing virus burden. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 diminished these effector activities in vitro and lessened virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity., Author summary In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelope glycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1 vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.

BACKGROUNDThe biological processes associated with post-acute sequelae of SARS-CoV-2 infection (PASC) are unknown.METHODSWe measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (90 days) timepoints. We defined PASC as the presence of one or more COVID-19-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed effects models with terms for PASC and early and late recovery time periods.RESULTSDuring early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including TNF-alpha (1.14-fold higher mean ratio, 95%CI 1.01-1.28, p=0.028) and IP-10 (1.28-fold higher mean ratio, 95%CI 1.01-1.62, p=0.038). Among those with PASC, there was a trend toward higher IL-6 levels during early recovery (1.28-fold higher mean ratio, 95%CI 0.98- 1.70, p=0.07) which became more pronounced in late recovery (1.44-fold higher mean ratio, 95%CI: 1.11-1.86, pCONCLUSIONSPersistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.

BACKGROUNDAs the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), attention has turned to characterizing post-acute sequelae of SARS-CoV-2 infection (PASC).METHODSFrom April 21 to December 31, 2020, we assembled a cohort of consecutive volunteers who a) had documented history of SARS-CoV-2 RNA-positivity; b) were ≥ 2 weeks past onset of COVID-19 symptoms or, if asymptomatic, first test for SARS-CoV-2; and c) were able to travel to our site in San Francisco. Participants learned about the study by being identified on medical center-based registries and being notified or by responding to advertisements. At 4-month intervals, we asked participants about physical symptoms that were new or worse compared to the period prior to COVID-19, mental health symptoms and quality of life. We described 4 time periods: 1) acute illness (0-3 weeks), 2) early recovery (3-10 weeks), 3) late recovery 1 (12-20 weeks), and 4) late recovery 2 (28-36 weeks). Blood and oral specimens were collected at each visit.RESULTSWe have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Some experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with ambulation and performance of usual activities. The median visual analogue scale value rating of general health was lower at 4 and 8 months (80, interquartile range [IQR]: 70-90; and 80, IQR 75-90) compared to prior to COVID-19 (85; IQR 75-90). Biospecimens were collected at nearly 600 participant-visits.CONCLUSIONAmong a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.