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- Infectious Diseases
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates
Maity et al., Molecular & Cellular Proteomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981268/
In this study, researchers examined the proteins expressed in cerebrospinal fluid (CSF) in nonhuman primates (NHPs) to better understand how COVID-19 infection can result in brain pathology, a common outcome. The study found that even in NHPs with minimal or mild COVID‑19, CSF proteins were significantly dysregulated compared with uninfected NHPs. Furthermore, the most affected proteins were enriched in the same brain regions that show lesions after COVID-19 infection, including the cerebral cortex, basal ganglia, and brain stem. Collectively, these regions have wide-ranging control over such crucial functions as cognition, motor control, and breathing, showing how even mild COVID-19 infection can result in significant neurological impairment. Supported by ORIP (P51OD011104, S10OD032453), NIGMS, NCI, and NICHD.
Late Gene Expression–Deficient Cytomegalovirus Vectors Elicit Conventional T Cells That Do Not Protect Against SIV
Hansen et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070102/
Cytomegalovirus (CMV)–based vaccines aim to exploit unique immunological adaptations, including host manipulation and immune evasion strategies. Translating CMV-based vaccines from rhesus macaques to humans requires translating the immune factors responsible for efficacy, as well as vaccine vectors that are sufficiently safe for widespread use. Researchers examined the impact of a stringent attenuation strategy on vector-induced immune protection against simian immunodeficiency virus (SIV) in rhesus macaques of both sexes. They reported that elicited CD8+ T cells exclusively failed to protect against SIV challenge. These data suggest that late viral gene expression and/or residual in vivo spreading are required to induce protective CD8+ T cell responses. Supported by ORIP (P51OD011092, P51OD011107, S10OD016261), NCI, NIAID, and NCATS.
Long-Term Evolutionary Adaptation of SIVcpz toward HIV-1 Using a Humanized Mouse Model
Schmitt et al., Journal of Medical Primatology. 2022.
https://www.doi.org/10.1111/jmp.12616
Chimpanzee-derived simian immunodeficiency viruses (SIVcpz) are thought to have evolved into the highly pathogenic HIV-1 Group M, but the genetic adaptations required for SIV progenitor viruses to become pathogenic and established as HIVs in the human population have remained unclear. Using humanized mice of both sexes, researchers mimicked the evolution of SIVcpz into HIV-1 Group M through serial passaging. After four generations, the researchers observed increased initial viral load, increased CD4+ T cell decline, and nonsynonymous substitutions. Overall, these data indicate increased viral fitness and pathogenicity. This work also demonstrates the utility of humanized mice in recreating the adaptive pressures necessary for the evolution of SIVcpz into HIV-1. Supported by ORIP (P51OD011104, P51OD011106), NCATS, and NIAID.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
Innate Immune Regulation in HIV Latency Models
Olson et al., Retrovirology. 2022.
https://www.doi.org/10.1186/s12977-022-00599-z
Researchers are interested in developing therapeutic approaches to target latent HIV reservoirs, which are unaffected by antiretroviral therapy. Previous studies suggest that HIV latency might be related to viral RNA sensing, interferon (IFN) signaling, and IFN-stimulated gene (ISG) activation. In this study, the researchers evaluated responses to stimulation by retinoic acid–inducible gene I agonists and IFN in multiple CD4+ T cell line models for HIV latency. The models represented various aspects of latent infection and viral control. Several of the cell lines demonstrated reduced ISG induction, suggesting that long-term latency might be related to dysregulation of the downstream IFN response. These effects likely reflect transcriptional changes occurring within a core set of ISGs and altering IFN responses. Additional studies could provide insight into the functions of these ISGs in HIV latency. Supported by ORIP (P51OD010425), NCATS, and NIAID.
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.
Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial
Stephenson et al., Nature Medicine. 2021.
https://doi.org/10.1038/s41591-021-01509-0
Researchers carried out a double-blind trial of one administration of the HIV-1 V3-glycan-specific antibody (Ab) PGT121 in HIV-uninfected and HIV-infected adults on antiretroviral therapy (ART), as well as an open-label trial of one infusion of PGT121 in viremic HIV-infected adults not on ART. The investigators observed no treatment-related serious adverse events among the 48 participants, and neutralizing anti-drug Abs were not elicited. PGT121 reduced plasma HIV RNA by a median of 1.77 log in viremic participants. Two individuals experienced ART-free viral suppression for ≥168 days following Ab infusion. These findings motivate further investigation of Ab-based therapeutic strategies for long-term HIV suppression. Supported by ORIP (R01OD024917, R01OD011095), NIAID, and NCATS.