The Biology of HIV Infections

National Institute Of Allergy And Infectious Diseases

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Abstract

BROADLY-ACTING NEUTRALIZING ANTIBODY IMMUNOTHERAPY INITIATED ON DAY 3 OR WEEK 2 AFTER SHIV INFECTION OF RHESUS MACAQUES CAN CONTROL VIREMIA FOR SEVERAL YEARS. We previously reported that combination bNAb immunotherapy initiated on day 3 post infection (PI) maintained durable CD8+ T cell-mediated suppression of SHIVAD8 viremia and pre-inoculation levels of CD4+ T cells in 6 of 13 treated monkeys during 3years of observation, as assessed by successive CD8+ T cell depletion experiments. These initial findings have been extended by monitoring the virologic and CD4+ T cell status of the original Day 3 treated controller monkeys during an additional 2.5 to 3.5 year period; and 2) initiating a new immunotherapy regimen in which the effects of combination bNAb alone, or cART plus bNAb treatment, beginning at week 2 post SHIV infection time point. During the 4th and 5th years after bNAb immunotherapy initiation on day 3 PI, 3 of the 7 original progressor animals) suppressed virus replication and became late controllers. In total, 9 of 13 animals starting combination bNAb immunotherapy on day 3 PI became controller macaques. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs), beginning at the clinically more relevant week 2 PI, were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8+ cells, which developed over a 3-year period. However, the median time to suppression of plasma viremia, following intervention on week 2, was markedly delayed (85 weeks) compared to combination bNAb immunotherapy initiated on day 3 (39 weeks). In both cases, the principal correlate of virus control was the induction of CD8+ T cellular immunity. PREVENTION AND TREATMENT OF SHIVAD8 INFECTION IN RHESUS MACAQUES BY A POTENT D PEPTIDE HIV ENTRY INHIBITOR. Combination anti-retroviral therapy (cART) has greatly improved the length and quality of life of HIV infected individuals with access to treatment and has reduced HIV transmission from treated patients. We have evaluated a potent 16-residue D-peptide (composed of D-amino acids) HIV-1 entry inhibitor, designated CPT31, which targets the highly conserved gp41 N-peptide pocket region, in blocking virus infections both in vitro and in vivo. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a SHIV macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by 2 logs before rebound occurred due to the emergence of drug resistance. In a second group of chronically infected animals, virus loads were initially suppressed to background levels following 6 weeks of treatment with combination cART, beginning at week 46 PI, followed by 13 weeks of CPT31 monotherapy. Rapid rebound of virus replication occurred at week 62 following cessation of daily D-peptide administration. Most interestingly, in 3 of the 4 chronically-infected CTP31 treated macaques, the levels of viremia gradually declined to undetectable levels by week 150 PI and remained durably controlled over the next 2 years (through week 242 PI). These data establish CPT31 as a promising new candidate for HIV prevention and treatment. A BROADLY NEUTRALIZING MACAQUE MONOCLONAL ANTIBODY AGAINST THE HIV-1 V3-GLYCAN PATCH. A small fraction of HIV-1 infected humans (Elite Neutralizers) develop potent broadly neutralizing antibodies (bNAbs) against HIV-1 that can protect macaques from infection with simian immunodeficiency HIV chimeric virus (SHIV). Similarly, a small number of macaques infected with SHIVs also develop broadly neutralizing serologic activity, but less is known about the nature of these simian antibodies. A monoclonal antibody, Ab1485, has been isolated from a macaque infected with SHIVAD8 that developed broadly neutralizing serologic activity mapping to the V3-glycan region of HIV-1 Env. Ab1485 neutralizes 38.1 % of HIV-1 isolates in a panel of 42 pseudoviruses with a geometric mean IC50 of 0.055 g/ml and SHIVAD8 with an IC50 of 0.028 g/ml. Ab1485 binds to the V3-glycan epitope in a glycan-dependent manner as determined by ELISA and neutralization assays with HIV-1JRCSF mutant viruses. A 3.5 cryo-electron microscopy structure of Ab1485 in complex with a native-like SOSIP Env trimer showed conserved contacts with the N332gp120 glycan and the gp120 GDIR peptide motif, but in a distinct Env-binding orientation relative to human V3/N332gp120 glycan-targeting bNAbs. Finally, intravenous infusion of Ab1485 protected macaques from a high dose intrarectal challenge with SHIVAD8. We conclude that macaques can develop bNAbs against the V3-glycan patch that resemble human V3-glycan bNAbs. SEQUENTIAL IMMUNIZATION ELICITS BROAD, BUT WEAKLY NEUTRALIZING, ANTI-HIV-1 ANTIBODIES TO THE VIRAL ENVELOPE V3-GLYCAN PATCH AND CD4BS IN RHESUS MACAQUES. Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus/antibody co-evolution. Sequential immunization with a V3-glycan-patch germline-targeting HIV-1 Env followed by variant Envs reproduced this process in mice carrying V3-glycan bNAb precursor B-cells. Eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit weak heterologous neutralizing sera and antibodies in non-human primates (NHPs). Structures of antibody/Env complexes following prime/boosts demonstrated target epitope recognition with apparent maturation to accommodate glycans, but increasing off-target antibodies with boosting. A single NHP remained uninfected after a SHIV challenge. Having shown that heterologous neutralization can be achieved using sequential immunization, the prime-boost regimens have been improved to increase bNAb potency and to significantly reduce off-targeting of non-conserved epitopes. Vaccination of three new cohorts of NHPs has recently been initiated targeting the CD4 binding site, the V3 glycan cluster, and a mosaic combination of the conserved CD4, V3 glycan and V2 epitopes.