A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Background: Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral ftness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in ftness losses. Results: Strongly selected mutations were identifed by analyzing 5′-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was frst detected at day 91 post screening and was fxed in the viral population at day 273 while the synonymous N323tc mutation was frst detected at day 177 and fxed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when ftness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a signifcant ftness loss while the N323tc mutation had little impact on viral ftness. Conclusions: The rapid fxation, the lack of detectable immune responses and the signifcant ftness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodie

Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection

Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines

The detector system of the Daya Bay reactor neutrino experiment

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SARS-CoV-2 and HIV-1: Should HIV-1-infected individuals in Sub-Saharan Africa be considered a priority group for the COVID-19 vaccines?

Since its emergence in 2019 SARS-CoV-2 has proven to have a higher level of morbidity and mortality compared to the other prevailing coronaviruses. Although initially most African countries were spared from the devastating effect of SARS-CoV-2, at present almost every country has been affected. Although no association has been established between being HIV-1-infected and being more vulnerable to contracting COVID-19, HIV-1-infected individuals have a greater risk of developing severe COVID-19 and of COVID-19 related mortality. The rapid development of the various types of COVID-19 vaccines has gone a long way in mitigating the devastating effects of the virus and has controlled its spread. However, global vaccine deployment has been uneven particularly in Africa. The emergence of SARS-CoV-2 variants, such as Beta and Delta, which seem to show some subtle resistance to the existing vaccines, suggests COVID-19 will still be a high-risk infection for years. In this review we report on the current impact of COVID-19 on HIV-1-infected individuals from an immunological perspective and attempt to make a case for prioritising COVID-19 vaccination for those living with HIV-1 in Sub-Saharan Africa (SSA) countries like Malawi as one way of minimising the impact of COVID-19 in these countries

Antisense-Derived HIV-1 cryptic Epitopes are not major drivers of viral evolution

While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I restricted epitope. The CE were evaluated for CD8 T cell responses in patients with chronic and acute HIV infection. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic, and acute infection respectively. The immunogenic CE were all derived from a single antisense reading frame within pol. However, when these CE were tested using longitudinal study samples, CE specific T cell responses were detected but did not consistently select for viral escapes. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. This latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, and magnitude of CE responses during acute infections. IMPORTANCE Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence supporting that targeting these epitopes to drive HIV escape mutations have been substantially limited and none have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I associated viral escape. Our data shows that cryptic epitopes are immunogenic during acute infection and many of these responses are elicited towards translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8 mediated immune escape. Nevertheless, improving cryptic epitope specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines

Antisense-derived HIV-1 cryptic epitopes are not major drivers of viral evolution during the acute phase of infection

While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I restricted epitope. The CE were evaluated for CD8 T cell responses in patients with chronic and acute HIV infection. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic, and acute infection respectively. The immunogenic CE were all derived from a single antisense reading frame within pol. However, when these CE were tested using longitudinal study samples, CE specific T cell responses were detected but did not consistently select for viral escapes. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. This latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, and magnitude of CE responses during acute infections

Sorby Architectural Photograph

Photograph of Freston Tower, Ipswic

Bayesian subset selection for threshold autoregressive moving-average models

Bayesian model averaging, Mixture normal distribution, Stochastic search variable selection method,