Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition

Abstract

In some instances, unsuppressed HIV has been associated with severe COVID-19 disease, but the mechanisms underpinning this susceptibility are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following PBMC stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4+T cell responses against the Spike protein compared to the viremic PLWH. Absolute CD4 count correlated positively with SARS-CoV-2 specific CD4+ and CD8+ T cell responses (CD4 r= 0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4+ T cell responses (CD4 r= -0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern.

SARS-CoV-2-Specific T Cell Responses in Immunocompromised Individuals with Cancer, HIV or Solid Organ Transplants

“…Although PLWH represent a particularly vulnerable patient population, the impact of T cell-mediated immunity in case of SARS-CoV-2 infection has not been fully elucidated in this cohort. Early results indicate impaired frequencies of SARS-CoV-2-specific CD4+ T cells producing IFN-γ and TNF-α in patients with unsuppressed HIV infection, compared to PLWH with controlled viremia ( Figure 3 B) [ 30 ]. However, no significant differences on the CD8+ T cell level were identified [ 30 ].…”

“…Early results indicate impaired frequencies of SARS-CoV-2-specific CD4+ T cells producing IFN-γ and TNF-α in patients with unsuppressed HIV infection, compared to PLWH with controlled viremia ( Figure 3 B) [ 30 ]. However, no significant differences on the CD8+ T cell level were identified [ 30 ]. Moreover, Adachi et al observed a transient decrease in CD4+ T cell, CD8+ T cell, and total lymphocyte counts during SARS-CoV-2 infection [ 114 ].…”

“…This also applies to patients co-infected with HIV and SARS-CoV-2 receiving ART, where suppressed HIV is associated with reduced COVID-19 severity and mortality ( Figure 3 A) [ 119 ]. Importantly, untreated PLWH exhibits a less effective immune response to SARS-CoV-2, compared to PLWH under ART and low viremia ( Figure 3 B) [ 30 , 119 , 120 ]. Indeed, it has recently been shown that, in contrast to uncontrolled HIV infection, PLWH with suppressed viral load exhibit similar SARS-CoV-2-specific CD4+ and CD8+ T cell responses with analogous cytokine expression, compared to healthy individuals [ 30 ].…”

“…Importantly, untreated PLWH exhibits a less effective immune response to SARS-CoV-2, compared to PLWH under ART and low viremia ( Figure 3 B) [ 30 , 119 , 120 ]. Indeed, it has recently been shown that, in contrast to uncontrolled HIV infection, PLWH with suppressed viral load exhibit similar SARS-CoV-2-specific CD4+ and CD8+ T cell responses with analogous cytokine expression, compared to healthy individuals [ 30 ]. In line, Alrubayyi et al were able to detect the development of SARS-CoV-2-specific CD4+ and CD8+ T cells in PLWH on ART and further describe a correlation between the CD4+/CD8+ ratio and the magnitude of SARS-CoV-2-specific T cell responses [ 120 ].…”

“…Considering results from the healthy population, the SARS-CoV-2-specific cellular immunity might be a major factor in determining the degree of protection in this vulnerable cohort. However, first data imply significantly attenuated virus-specific T cell responses following SARS-CoV-2 infection [ 28 , 29 , 30 ] and vaccination [ 31 , 32 , 33 , 34 , 35 ], in patients suffering from disease-related or iatrogenic immunosuppression. In addition, current guidelines regarding the management of SARS-CoV-2 in these high-risk populations mostly originate from clinical observations, while evidence-based recommendations are limited.…”