Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research.

UNLABELLED: Eliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected "fan blade" motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine. IMPORTANCE: At present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers, binds to many of the well-characterized broad neutralizing MAbs that target conserved Env epitopes, and induce cross-subtype neutralizing antibodies as measured in both cell line and primary cell assays. This subtype C Env gp145 protein is currently undergoing good manufacturing practice production for use as a reagent for preclinical studies and for human clinical research. This product will serve as a reagent for comparative studies and may represent a next-generation candidate HIV immunogen.

Current advances and challenges in HIV-1 vaccines.

Recent advances in science, which have aided HIV-1 vaccine development, include an improved understanding of HIV-1 envelope structure and function, expansion of the pipeline with innovative vaccine strategies, promising multi-gene and multi-clade vaccines that elicit cellular immunity, conduct of clinical trials in a global network, and development of validated techniques that enable simultaneous measurement of multiple T cell vaccine-induced immune responses in humans. A common feature of several preventive vaccine strategies now in early clinical trials is their ability in nonhuman primates to attenuate clinical disease rather than completely prevent HIV-1 infection. One vaccine concept has been tested in large-scale clinical trials, two are currently in efficacy trials, and one more is poised to enter efficacy trial in the next few years. Simultaneously, expanded efforts continue to identify new designs that induce mucosal immunity as well as broadly neutralizing antibodies.

Acyclovir sensitivity of sequential herpes simplex virus type 2 isolates from the genital mucosa of immunocompetent women.

BACKGROUND: Despite widespread use of acyclovir, infection with acyclovir-resistant herpes simplex virus type 2 (HSV-2) remains uncommon. To understand the frequency and clinical significance of acyclovir-resistant isolates, we evaluated the in vitro acyclovir sensitivities of sequential isolates from 34 immunocompetent women. METHODS: HSV-2-seropositive women collected daily samples of genital secretions while receiving acyclovir or placebo, each for 10 weeks. In vitro acyclovir sensitivity testing was performed using the dye uptake assay; isolates for which the concentration of acyclovir that inhibited cytopathic effect by 50% (EC50) was > or = 3 microg/mL were defined as resistant. RESULTS: A total of 351 isolates from 26 women were tested (median, 10 isolates/woman [range, 3-45 isolates/woman]). The median EC50 was 0.91 microg/mL. Overall, 7 isolates (1.7%) from 6 women had EC50 values > or = 3 microg/mL. None of the women was receiving acyclovir when the acyclovir-resistant isolates were detected. Acyclovir-sensitive and acyclovir-resistant isolates were detected in samples collected on the same day from separate anatomic sites in 3 women. The acyclovir-resistant isolates were transient, because acyclovir-sensitive isolates were obtained before and after the acyclovir-resistant isolates from 5 women were detected. CONCLUSIONS: Among immunocompetent women, the finding of acyclovir-resistant HSV-2 isolates likely represents transient mucosal variants and does not predict treatment failure.