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Long- Covid in PLWH & Immune Responses in PLWH
Recovering From COVID Prior to Vaccine Availability
  This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Michael J. Peluso,1 Matthew A. Spinelli,1 Tyler-Marie Deveau,2 Carrie A. Forman,1 Sadie E. Munter,23 Sujata Mathur,3 Alex F. Tang,1 Scott Lu,3 Sarah A. Goldberg,3 Mireya I. Arreguin, 1 Rebecca Hoh,14 Jessica Y. Chen, 1 Enrique O. Martinez, 1 Ahmed Chenna, 4 John W. Winslow, 4 Christos J.5 Petropoulos,4 Alessandro Sette,5,6 Daniella Weiskopf,5 Nitasha Kumar,2 Kara L. Lynch, 7 Peter W.6 Hunt,2 Matthew S. Durstenfeld, 8 Priscilla Y. Hsue,8 J. Daniel Kelly,3 Jeffrey N. Martin,3 David V.7 Glidden,3 Monica Gandhi,1 Steven G. Deeks,1 Rachel L. Rutishauser2*, Timothy J. Henrich2*
"HIV status was strongly associated with PASC (odds ratio 4.01, p=0.008)"

Among PWH, we found broadly similar SARS-CoV-2-specific antibody and T cell immune 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 the proportion of PD-1+ CD4+ T cells and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms.
Conclusions We identified potentially important differences in SARS-CoV-2-specific CD4+ and CD8+ T cells 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.
In this study, we sought to characterize SARS-CoV-2 specific immune responses and the presence of persistent symptoms in a cohort of PWH with a history of COVID-19 prior to the availability of vaccination in comparison to a similar group of HIV-negative individuals recovering from COVID-19. We hypothesized that PASC would be more prevalent among PWH and that this would be driven by reduced SARS-CoV-2 specific immune responses and increased indices of systemic inflammation among this population.
We found that post-acute COVID-19-attributed symptoms were common in this cohort of mostly ART-treated PWH recovering from SARS-CoV-2 infection. HIV status was strongly associated with PASC, raising concerns that this condition might be common among PWH recovering from COVID-19. Among those living with HIV, we observed broadly similar SARS-CoV-2-specific antibody and T cell immune responses as compared with a well-matched group of HIV-negative individuals, and higher levels of markers of inflammation that were also associated with PASC. Finally, we observed potentially important differences in SARS-CoV-2 specific CD4+ and CD8+ T cells that might have implications for long-term immunity conferred by natural infection. This analysis adds to the limited published data examining SARS-CoV-2-specific immune responses in PWH and underscores the need for larger and more detailed studies of PASC in this population.
There are biological reasons why PWH might be particularly predisposed to developing PASC. One leading hypothesis is that PASC is driven, at least in part, by residual or ongoing inflammation following SARS-CoV-2 infection [17-20]. Even with suppressive ART, HIV is a chronic inflammatory condition that can be associated with complications of persistent immune activation [33-39]. If a higher prevalence of PASC among PWH recovering from COVID-19 is confirmed in larger epidemiologic studies, one possible explanation could be that this is driven in part by immune dysregulation from SARS-CoV-2 infection compounded upon higher baseline inflammation from HIV infection, which in turn could drive organ system dysfunction and the experience of somatic symptoms. In addition to elevated inflammatory responses, additional factors that could potentially predispose PWH to PASC include an increased frequency of autoimmune phenomena [57-59], localized tissue inflammation related to mucosal and endothelial injury [31,32], and other syndemic comorbidities including substance use [60,61] and metabolic disorders [62-64]. Furthermore, reactivation of latent human herpes viruses, such as Epstein Barr Virus or Cytomegalovirus (CMV) during acute SARS-CoV-2 infection may further perturb immune dysregulation and promote inflammation. PWH tend to have higher rates of CMV infection than HIV-negative individuals and this is thought to drive, in part, chronic inflammation in treated HIV and may lead to impaired CD8+ T cell function. Regardless of the mechanism, our observation is of importance because it suggests that PASC may be especially common in PWH and emphasizes the urgent need for larger studies of PASC in this population, which are underway [65].
This study has several limitations. The sample size was small, as relatively few PWH were infected with SARS-CoV-2 during the first year of the pandemic in our geographic area [73]. As there were few PWH without PASC, we were likely underpowered to make comparisons within the PWH sub-group; larger cohorts will be needed to do so. see below for full discussion of limitations

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