Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection.

UNLABELLED: A fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol 85:5804-5813, 2011, http://dx.doi.org/10.1128/JVI.02482-10). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The neutralization breadth was positively associated with time postinfection (P = 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID50) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches. IMPORTANCE: There are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs.

Definition of an 18-mer Synthetic Peptide Derived from the GB virus C E1 Protein as a New HIV-1 Entry Inhibitor.

BACKGROUND: A slower progression of AIDS and increased survival in GBV-C positive individuals, compared with GBV-C negative individuals has been demonstrated; while the loss of GBV-C viremia was closely associated with a rise in mortality and increased progression of AIDS. Following on from the previous reported studies that support the thesis that GBV-C E2 interferes with HIV-1 entry, in this work we try to determine the role of the GBV-C E1 protein in HIV-1 inhibition. METHODS: The present work involves the construction of several overlapping peptide libraries scanning the GBV-C E1 protein and the evaluation of their anti-HIV activity. RESULTS: Specifically, an 18-mer synthetic peptide from the GBV-C E1 protein, E1(139-156), showed similar antiviral activity against HIVs from viruses from clades A, B, C, D and AE. Competitive ELISA using specific gp41-targeting mAbs, fluorescence resonance energy transfer as well as haemolysis assays demonstrated that this E1 peptide sequence interacts with the highly conserved N-terminal region of the HIV-1 gp41 (the fusion peptide) which is essential for viral entry. CONCLUSIONS: We have defined a novel peptide lead compound and described the inhibitory role of a highly conserved fragment of the E1 protein. GENERAL SIGNIFICANCE: The results together allow us to consider the non-pathogenic E1 GBV-C protein as an attractive source of peptides for the development of novel anti-HIV therapies.

Broadly cross-neutralizing antibodies in HIV-1 patients with undetectable viremia.

Several recent studies have identified HIV-infected patients able to produce a broad neutralizing response, and the detailed analyses of their sera have provided valuable information to improve future vaccine design. All these studies have excluded patients on antiretroviral treatment and with undetectable viral loads, who have an improved B cell profile compared to untreated patients. To better understand the induction of neutralizing antibodies in patients on antiretroviral treatment with undetectable viremia, we have screened 508 serum samples from 364 patients (173 treated and 191 untreated) for a broadly neutralizing antibody (bNAb) response using a new strategy based on the use of recombinant viruses. Sera able to neutralize a minipanel of 6 recombinant viruses, including envelopes from 5 different subtypes, were found in both groups. After IgG purification, we were able to confirm the presence of IgG-associated broadly neutralizing activity in 3.7% (7 of 191) of untreated patients with detectable viremia and 1.7% (3 of 174) of aviremic patients receiving antiretroviral treatment. We thus confirm the possibility of induction of a broad IgG-associated neutralizing response in patients on antiretroviral treatment, despite having undetectable viremia. This observation is in stark contrast to the data obtained from long-term nonprogressors, whose little neutralizing activity has been attributed to the low levels of viral replication.