Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features.

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

Lower SARS-CoV-2-specific humoral immunity in people living with HIV-1 recovered from nonhospitalized COVID-19.

People living with HIV-1 (PLWH) exhibit more rapid antibody decline following routine immunization and elevated baseline chronic inflammation than people without HIV-1 (PWOH), indicating potential for diminished humoral immunity during SARS-CoV-2 infection. Conflicting reports have emerged on the ability of PLWH to maintain humoral protection against SARS-CoV-2 coinfection during convalescence. It is unknown whether peak COVID-19 severity, along with HIV-1 infection status, associates with the quality and quantity of humoral immunity following recovery. Using a cross-sectional observational cohort from the United States and Peru, adults were enrolled 1-10 weeks after SARS-CoV-2 infection diagnosis or symptom resolution. Serum antibodies were analyzed for SARS-CoV-2-specific response rates, binding magnitudes, ACE2 receptor blocking, and antibody-dependent cellular phagocytosis. Overall, (a) PLWH exhibited a trend toward decreased magnitude of SARS-CoV-2-specific antibodies, despite modestly increased overall response rates when compared with PWOH; (b) PLWH recovered from symptomatic outpatient COVID-19 had comparatively diminished immune responses; and (c) PLWH lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when asymptomatic versus symptomatic outpatient disease was compared.

Identification of naturally processed CD4 T cell epitopes from the prostate-specific antigen kallikrein 4 using peptide-based in vitro stimulation.

Kallikrein (KLK)4 is a recently described member of the tissue kallikrein gene family that is specifically expressed in normal and prostate tumor tissues. The tissue-specific expression profile of this molecule suggests that it might be useful as a vaccine candidate against prostate cancer. To examine the presence of CD4 T cells specific for KLK4 in PBMC of normal individuals, a peptide-based in vitro stimulation protocol was developed that uses overlapping KLK4-derived peptides spanning the majority of the KLK4 protein. Using this methodology, three naturally processed CD4 epitopes derived from the KLK4 sequence are identified. These epitopes are restricted by HLA-DRB1*0404, HLA-DRB1*0701, and HLA-DPB1*0401 class II alleles. CD4 T cell clones specific for these epitopes are shown to efficiently and specifically recognize both recombinant KLK4 protein and lysates from prostate tumor cell lines virally infected to express KLK4. CD4 T cells specific for these KLK4 epitopes are shown to exist in PBMC from multiple male donors that express the relevant class II alleles, indicating that a CD4 T cell repertoire specific for KLK4 is present and potentially expandable in prostate cancer patients. The demonstration that KLK4-specific CD4 T cells exist in the peripheral circulation of normal male donors and the identification of naturally processed KLK4-derived CD4 T cell epitopes support the use of KLK4 in whole gene-, protein-, or peptide-based vaccine strategies against prostate cancer. Furthermore, the identification of naturally processed KLK4-derived epitopes provides valuable tools for monitoring preexisting and vaccine-induced responses to this molecule.