Virologists need to reclaim the gain of function debate from politicians and set up streamlined international guidelines to work on viruses with pandemic potential. Read more in this @Nature opinion piece by @TheOttLab, @Virus_Immunity, and myself: https://t.co/D1e6VCGbF0

Treatments that target the immune system to control autoimmunity or cancer are on the rise. Also, advanced HIV disease may be seen as someone else's problem. We don't know how a future pandemic will interact with immunocompromise, but the news is unlikely to be good.

We discuss the possible relationship between the numbers of immunocompromised people and the emergence of highly mutated variants of SARS-CoV-2. If they are the product of evolution in one person, variants have a high element of chance in when they emerge, disrupting seasonality.

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The review, with @rjlessells and @richardneher, considers unique features of persistent infections, which give enough time for viral mutants to be selected and become dominant in one person. Because there are more, they have a much higher chance to transmit to the next person.

We have a new Nature Reviews Micro. paper out which focusses on SARS-CoV-2 persistence in immunocompromised people, especially those with advanced HIV disease. We consider why such infections likely produce variants and interfere with seasonality. https://t.co/5LvgGxN20R

There is a bunch of cool stuff in there, but somewhere we wrote that if participants get one new collaboration, the meeting would be a success. This is what happened to me - I got a collaborator on mpox, not knowing this would change my lab's focus just a few months later!

I want to share a keystone Emerging Viruses meeting report just out in Nature Microbiology which was written by @TheOttLab, @Virus_Immunity, @sigallab and Priti Kumar at Yale, with great contributions by Francisco Zapatero-Belinchón from the Ott lab. https://t.co/CLdNFf7dzc

I want to thank the lead author @Afrah_Khairalla, @Zesuliwe_Jule, Alice Piller, @KajalReedoy, @YashiG24, @farinakarim, @KhadijaKhan24, and our collaborators for the terrific effort. It would not be possible without the Gates Foundation Global Health Discovery Collaboratory

Therefore, people with severe Covid-19 made strong neutralizing antibody responses after infection. But people with non-severe disease could make comparable responses, with similar proteomic profiles. If we learn what makes for a strong response, we might be able to harness it.

Using HSPA8 levels, we could reasonably predict at infection who would make a strong neutralizing antibody response at convalescence:

Differentially expressed proteins in high vs low neutralizers included those involved in SARS-CoV-2 infection, including furin (viral fusion), and HSPA8, (clathrin-mediated endocytosis). Furin was common to the neutralization and disease severity responses (in green below)

We measured people's neutralizing antibodies post-infection. We determined whether they had severe vs non-severe disease by whether they needed supplemental oxygen. The high neutralizer group included people on supplemental oxygen, but also some with non-severe disease

We submitted our work about what determines the strength of the neutralizing antibody response in Covid-19. https://t.co/nG34HeBazm We found proteomic signatures for strong neutralizing responses. Severe Covid-19 made a strong response more likely but it was not essential.

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I want to thank the lead author @farinakarim, @KhadijaKhan24, @LustigGil, @Zesuliwe_Jule and all the laboratory and clinical team, T cell collaborators Catherine Riou and Wendy Burgers, and @PennyMo70026063, @rjlessells, @Tuliodna, and especially our partner Yunus Moosa

Bottom line, in persistent SARS-CoV-2 infections, neutralizing antibodies are likely key to clearance. This likely applies when a pandemic and high HIV prevalence intersect. With low ART adherence, you will get evolution, and perhaps adaptation, of the pandemic virus.

Through a close collaboration, Wendy Burgers and Catherine Riou at University of Cape Town checked whether clearance was associated with T cell responses. There were too few CD4 T cells to test, but enough CD8 T cells (bottom population below). These did not appear at clearance:

In the previous figure, top row showed the course of SARS-CoV-2 infection in each participants, which lasted for between 130 to 293 days. Bottom row shows the measured neutralization capacity at different timepoints per participant against virus isolated from each participant.

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Eventually, all five participants adhered to antiretroviral therapy and controlled their HIV infection. As they did this, they cleared their SARS-CoV-2 infection. The immune response which most closely associated with clearance was the appearance of neutralizing antibodies:

Investigating five advanced HIV disease participants in depth, we observed that these persistent SARS-CoV-2 infections led to extensive SARS-CoV-2 evolution measured in terms of accumulated mutations:

In our cohort we followed people after SARS-CoV-2 infection in Durban, South Africa, including people immunosuppressed because of advanced HIV disease who had delayed adherence to antiretroviral therapy to suppress HIV. We found this group had much longer SARS-CoV-2 infections: