Profile of SARS-CoV-2-specific CD4 T cell response: Relationship with disease severity and impact of HIV-1 and active<i>Mycobacterium tuberculosis</i>co-infection

Riou, Catherine; Bruyn, Elsa Du; Stek, Cari; Daroowala, Remy; Goliath, René; Abrahams, Fatima; Said-Hartley, Qonita; Allowed, Brian W; Hsiao, Marvin; Wilkinson, Katalin A.; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Wasserman, Sean; Wilkinson, Robert J.

doi:10.1101/2021.02.16.21251838

Cited by 8 publications

(8 citation statements)

References 71 publications

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“…Describing mortality risk among these groups is important because studies have shown that among patients with SARS-CoV-2 infection, those who also had HIV and tuberculosis had altered T-cell functions and were at risk of more severe disease. 28 Large population cohorts from the Western Cape province of South Africa 18 and the UK 19,20 and more recent metaanalyses [21][22][23] found people with HIV to have an increased risk of COVID-19 mortality, with increased in-hospital mortality reported in the Western Cape 18 and UK 19 studies. Our study, however, could not conclude that HIV is a risk factor at the population level.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study

Jassat¹,

Cohen²,

Tempia³

et al. 2021

The Lancet HIV

136

141

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Background The interaction between COVID-19, non-communicable diseases, and chronic infectious diseases such as HIV and tuberculosis is unclear, particularly in low-income and middle-income countries in Africa. South Africa has a national HIV prevalence of 19% among people aged 15-49 years and a tuberculosis prevalence of 0•7% in people of all ages. Using a nationally representative hospital surveillance system in South Africa, we aimed to investigate the factors associated with in-hospital mortality among patients with COVID-19. MethodsIn this cohort study, we used data submitted to DATCOV, a national active hospital surveillance system for COVID-19 hospital admissions, for patients admitted to hospital with laboratory-confirmed SARS-CoV-2 infection between March 5, 2020, and March 27, 2021. Age, sex, race or ethnicity, and comorbidities (hypertension, diabetes, chronic cardiac disease, chronic pulmonary disease and asthma, chronic renal disease, malignancy in the past 5 years, HIV, and past and current tuberculosis) were considered as risk factors for COVID-19-related in-hospital mortality. COVID-19 in-hospital mortality, the main outcome, was defined as a death related to COVID-19 that occurred during the hospital stay and excluded deaths that occurred because of other causes or after discharge from hospital; therefore, only patients with a known in-hospital outcome (died or discharged alive) were included. Chained equation multiple imputation was used to account for missing data and random-effects multivariable logistic regression models were used to assess the role of HIV status and underlying comorbidities on COVID-19 in-hospital mortality. FindingsAmong the 219 265 individuals admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and known in-hospital outcome data, 51 037 (23•3%) died. Most commonly observed comorbidities among individuals with available data were hypertension in 61 098 (37•4%) of 163 350, diabetes in 43 885 (27•4%) of 159 932, and HIV in 13 793 (9•1%) of 151 779. Tuberculosis was reported in 5282 (3•6%) of 146 381 individuals. Increasing age was the strongest predictor of COVID-19 in-hospital mortality. Other factors associated were HIV infection (adjusted odds ratio 1•34, 95% CI 1•27-1•43), past tuberculosis (1•26, 1•15-1•38), current tuberculosis (1•42, 1•22-1•64), and both past and current tuberculosis (1•48, 1•32-1•67) compared with never tuberculosis, as well as other described risk factors for COVID-19, such as male sex; non-White race; underlying hypertension, diabetes, chronic cardiac disease, chronic renal disease, and malignancy in the past 5 years; and treatment in the public health sector. After adjusting for other factors, people with HIV not on antiretroviral therapy (ART; adjusted odds ratio 1•45, 95% CI 1•22-1•72) were more likely to die in hospital than were people with HIV on ART. Among people with HIV, the prevalence of other comorbidities was 29•2% compared with 30•8% among HIV-uninfected individuals. Increasing number of comorbidities was associated with...

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Section: Discussionmentioning

confidence: 99%

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study

Jassat¹,

Cohen²,

Tempia³

et al. 2021

The Lancet HIV

136

141

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“…There is some evidence that HIV is associated with an increased risk of more severe disease and death from COVID-19 17 , although in most studies the association is modest 36-39 . Two studies from South Africa have demonstrated that HIV is associated with suboptimal CD4+ T-cell and humoral immune responses to SARS-CoV-2, particularly in the absence of suppressive ART 17,40 ; and one study from the United States suggested that HIV is associated with lower neutralizing antibody titres following natural infection 41 . In the case described here, based on the very low CD4+ count there was putative immunosuppression as a result of antiretroviral treatment failure and HIV drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection

Karim

Moosa

Gosnell

et al. 2021

Preprint

103

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While most people effectively clear SARS-CoV-2, there are several reports of prolonged infection in immunosuppressed individuals. Here we present a case of prolonged infection of greater than 6 months with the shedding of high titter SARS-CoV-2 in an individual with advanced HIV and antiretroviral treatment failure. Through whole-genome sequencing at multiple time points, we demonstrate the early emergence of the E484K substitution associated with escape from neutralizing antibodies, followed by other escape mutations and the N501Y substitution found in most variants of concern. This provides support to the hypothesis of intra-host evolution as one mechanism for the emergence of SARS-CoV-2 variants with immune evasion properties.

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“…Moreover, T cell responses can confer protection even in the absence of humoral responses, given that, patients with inherited B cell deficiencies or hematological malignancies are able to fully recover from SARS-CoV-2 infection ( 22 ). In some instances, COVID-19 disease severity has been attributed to poor SARS-CoV-2-specific CD4 + T cell polyfunctionality potential, reduced proliferation capacity and enhanced HLA-DR expression ( 14 ). Importantly, a recent study identified nonsynonymous mutations in known MHC-1-restricted CD8 + T cell epitopes following deep sequencing of SARS-CoV-2 viral isolates from patients, demonstrating the capacity of SARS-CoV-2 to escape from CTL recognition ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

“…Larger epidemiological studies have demonstrated increased hospitalization and higher rates of COVID-19-related deaths among PLWH compared with HIV negative individuals (10)(11)(12)(13). Other studies have linked HIV mediated CD4⁺ T cell depletion to suboptimal T cell and humoral immune responses to SARS-CoV-2 (14). A recent study showed prolonged shedding of high titre SARS-CoV-2 and emergence of multiple mutations in an individual with advanced HIV and antiretroviral treatment (ART) failure (15).…”

Section: Introductionmentioning

confidence: 99%

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

Nkosi

Chasara

Mbatha

et al. 2022

Preprint

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HIV infection has been identified as one of the major risk factors for severe COVID-19 disease, but the mechanisms underpinning this susceptability 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+ and CD8+ 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.One sentence summaryUnsuppressed HIV infection is associated with muted SARS-CoV-2 T cell responses and poorer recognition of the Beta variant.

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Profile of SARS-CoV-2-specific CD4 T cell response: Relationship with disease severity and impact of HIV-1 and activeMycobacterium tuberculosisco-infection

Cited by 8 publications

References 71 publications

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study

Risk factors for COVID-19-related in-hospital mortality in a high HIV and tuberculosis prevalence setting in South Africa: a cohort study

Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection

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

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