Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

In this vaccine trial, few serious social harms were reported. Those who conduct HIV tests for insurance, employment, health care, or other reasons should be made aware that HIV vaccines can cause false-positive HIV test results. Those planning future trials must continue to provide needed support to volunteers. Social harms should be monitored with the same vigilance accorded to physical harms.

The NIAID-sponsored AIDS Vaccine Evaluation Group was established in 1988 to perform phase I/II clinical trials with candidate preventive HIV-1 vaccines. This report includes safety data from 1398 HIV-negative, healthy volunteers who were enrolled into 25 phase I and 1 phase H multicentered, randomized, double-blind studies evaluating seven recombinant HIV-1 envelope vaccines, two V3 loop synthetic peptide vaccines, and two live poxvirus-vectored recombinant envelope vaccines. All studies but three were placebo controlled; the placebo was either the adjuvant alone or, in studies of recombinant poxvirus vaccines, it was the vector with no gene insert or a non-HIV gene insert. All candidate vaccines were generally well tolerated. The only adverse effects that were clearly related to vaccination were occasional acute local and systemic reactions that were associated with the adjuvants. Three adjuvants in particular were associated with moderate to severe local reactions: alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), and QS21 (Genentech, Inc.). MTP-PE was also associated with self-limited severe systemic reactions. There were no serious adverse laboratory toxicities and no evidence of significant immunosuppressive events after receipt of the candidate vaccines. A few volunteers experienced symptoms that might relate to an underlying immunopathologic mechanism (rash, hemolytic anemia, arthralgia), but their presentations were mild and their incidence was low. Eleven volunteers were diagnosed with malignancies during or after their participation, which was within the 95% confidence interval of the number of cases predicted by the National Cancer Institute SEER (Program for cancer surveillance, epidemiology, and end result reporting) database. In conclusion, the envelope-based recombinant or synthetic candidate HIV-1 vaccines appear to be safe and this work has prepared the way for the testing of increasingly complex candidate HIV-1 vaccines.

Background The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention. Methods In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1–uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector. Results All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61). Conclusions Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired. Clinical Trials Registration South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27–0715–4917) and ClinicalTrials.gov (NCT02997969).

We evaluated prime-boost immunization with two recombinant envelope glycoprotein subunit vaccines (HIV-1MN recombinant gp160 vaccine in alum adjuvant [MN rgp160] and HIV-1MN recombinant gp120 vaccine in alum adjuvant [MN rgp120]) for safety and immunogenicity in healthy, HIV-1-uninfected adults. The rationale was to combine the helper T cell memory and binding antibody responses typically induced by rgp160 vaccines with the superior neutralizing antibody responses induced by rgp120 vaccines. In a double-blinded, controlled trial, volunteers were randomly assigned to receive MN rgp160 or adjuvant placebo, and a subset later received MN rgp120. The two vaccines were safe, but reactions to MN rgp160 and its adjuvant placebo exceeded those to MN rgp120. MN rgp160 induced IgG binding antibodies, including all IgG subclasses, to MN rgp160 in all vaccine recipients. HIV-1MN-neutralizing and anti-V3 MN peptide-binding antibodies were observed in a majority of volunteers after the fourth MN rgp160 immunization, but at lower levels compared with immunization with MN rgp120 in historical controls. HIV-1-binding, neutralizing, and fusion inhibition antibodies were boosted to the highest levels among MN rgp160 recipients after MN rgp120 booster injections. MN rgp120 boosting appeared to alter the distribution of MN rgp160 vaccine-induced, anti-MN rgp160 IgG subclass antibodies. MN rgp160 induced helper T cell memory, measured by lymphocyte proliferation, Thl and Th2 cytokine production, and skin testing. Strategies including both subunit vaccines may help maximize antibody and helper T cell memory responses to HIV-1 envelope glycoprotein.