Immunogenicity of COVID-19 vaccines and their effect on HIV reservoir in older people with HIV.

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. Our study on 68 PWH and 23 HIV-negative participants aged 55 and older post-three vaccine doses showed equally strong anti-spike IgG responses in serum and saliva through week 48 from baseline, while PWH salivary IgA responses were low. PWH had diminished live-virus neutralization responses after two vaccine doses, which were 'rescued' post-booster. Spike-specific T cell immunity was enhanced in PWH with normal CD4+ T cell count, suggesting Th1 imprinting. The frequency of detectable HIV viremia increased post-vaccination, but vaccines did not affect the size of the HIV reservoir in most PWH, except those with low-level viremia. Thus, older PWH require three doses of COVID-19 vaccine for maximum protection, while individuals with unsuppressed viremia should be monitored for adverse reactions from HIV reservoirs.

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV.

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4 + T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV - participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were 'rescued' after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV - participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral 'blips' in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4 + T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

Longitudinal Assessment of SARS-CoV-2-Specific T Cell Cytokine-Producing Responses for 1 Year Reveals Persistence of Multicytokine Proliferative Responses, with Greater Immunity Associated with Disease Severity.

Cell-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected survivors over a 1-year post-symptom onset (PSO) interval by ex vivo cytokine enzyme-linked immunosorbent spot assay (ELISpot) assay. All subjects demonstrated SARS-CoV-2-specific gamma interferon (IFN-γ), interleukin 2 (IL-2), and granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4+ T cells, targeted all structural proteins (nucleocapsid, membrane, and spike) except envelope, with GzmB and IL-2 greater than IFN-γ. Mathematical modeling predicted that (i) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, (ii) severe illness was associated with reduced IFN-γ and GzmB but increased IL-2 production rates, and (iii) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time, with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modeled to be 139 days (~4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the nucleocapsid and membrane regions. Both SARS-CoV-2-specific CD4+ and CD8+ T cell clones were able to kill target cells, though CD8 tended to be more potent. IMPORTANCE Our findings highlight the relative importance of SARS-CoV-2-specific GzmB-producing T cell responses in SARS-CoV-2 control and shared CD4 and CD8 immunodominant epitopes in seasonal coronaviruses or SARS-CoV-1, and they indicate robust persistence of T cell memory at least 1 year after infection. Our findings should inform future strategies to induce T cell vaccines against SARS-CoV-2 and other coronaviruses.

Protein kinase A type II-α regulatory subunit regulates the response of prostate cancer cells to taxane treatment.

In the last decade taxane-based therapy has emerged as a standard of care for hormone-refractory prostate cancer. Nevertheless, a significant fraction of tumors show no appreciable response to the treatment, while the others develop resistance and recur. Despite years of intense research, the mechanisms of taxane resistance in prostate cancer and other malignancies are poorly understood and remain a topic of intense investigation. We have used improved mutagenesis via random insertion of a strong promoter to search for events, which enable survival of prostate cancer cells after Taxol exposure. High-throughput mapping of the integration sites pointed to the PRKAR2A gene, which codes for a type II-α regulatory subunit of protein kinase A, as a candidate modulator of drug response. Both full-length and N-terminally truncated forms of the PRKAR2A gene product markedly increased survival of prostate cancer cells lines treated with Taxol and Taxotere. Suppression of protein kinase A enzymatic activity is the likely mechanism of action of the overexpressed proteins. Accordingly, protein kinase A inhibitor PKI (6-22) amide reduced toxicity of Taxol to prostate cancer cells. Our findings support the role of protein kinase A and its constituent proteins in cell response to chemotherapy.

Retroposons of salmonoid fishes (Actinopterygii: Salmonoidei) and their evolution.

Short and long retroposons, or non-LTR retrotransposons (SINEs and LINEs, respectively) are two groups of interspersed repetitive elements amplifying in the genome via RNA and cDNA-mediated reverse transcription. In this process, SINEs entirely depend on the enzymatic machinery of autonomous LINEs. The impact of retroposons on the host genome is difficult to overestimate: their sequences account for significant portion of the eukaryotic genome, while propagation of their active copies gradually reshapes it. In this way, the retropositional activity plays a role of important evolutionary factor. More than 100 LINE and nearly 100 SINE families have been described to date from the genomes of various eukaryotes, and it is salmonoid fishes (Actinopterygii: Salmonoidei) that are particularly noticeable for the diversity of transposons they host in their genomes, including two LINE and seven SINE families. Moreover, this group of ray-finned fish represents an excellent opportunity to study such a rare evolutionary phenomenon as lateral gene transfer, due to a great variety of transposons and other sequences salmons share with a blood fluke, Schistosoma japonicum (Trematoda: Strigeiformes)--a parasitic helminth infecting various vertebrates. The aim of the present review is to structure all knowledge accumulated about salmonoid retroposons by now, as well as to complement it with the new data pertaining to the distribution of some SINE families.

Novel SINE families from salmons validate Parahucho (Salmonidae) as a distinct genus and give evidence that SINEs can incorporate LINE-related 3'-tails of other SINEs.

Short interspersed elements (SINEs) constitute a group of retroposons propagating in the genome via a mechanism of reverse transcription, in which they depend on the enzymatic machinery of long retroposons (LINEs). Over 70 SINE families have been described to date from the genomes of various eukaryotes. Here, we characterize two novel SINEs from salmons (Actinopterygii: Salmonoidei). The first family, termed SlmI, was shown to be widespread among all genera of the suborder. These SINEs have a tRNA(Leu)-related promoter region at their 5'-end, a unique central conserved domain with a subfamily-specific region, and an end with RSg-1-LINE-derived 3'-terminus preceding the A/T-rich tail. The same LINE-related segment is also shared by two other salmonid SINEs: HpaI and OS-SINE1. The structural peculiarities and overall sequence identity of the SlmI 3'-terminus suggest that it has been acquired from HpaI SINEs but not directly from the partner LINE. This region plays a crucial role in the process of retrotransposition of short interspersed elements, and the case of its SINE-to-SINE transmission is the first recorded to date. Possible scenarios and potential evolutionary implications of the observed interaction between short retroposons are discussed. Apart from the above, we found a copy of the SlmI SINE in the GenBank entry for the blood fluke, Schistosoma japonicum (Trematoda: Strigeiformes) -- a trematode causing one of the most important human helminth infections, with its genome known to host other groups of salmonoid retroposons. In the present article, we suggest our views with regard to possible ways in which such an intensive horizontal transfer of salmonoid retroposons to the schistosomal genome occurs. The second novel SINE family, termed SlmII, originates from one of the SlmI subfamilies, with which it shares the same tRNA-related region, central domain, and a part of RSg-1-derived segment, but has a different 3'-tail of unidentified origin. Its distribution among salmonids validates Parahucho (Japanese huchen) as a distinct monotypic genus.