To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.

We studied the effect of entry inhibitors on 58 virus isolates derived during acute and chronic infection to validate these inhibitors in vitro and to probe whether viruses at early and chronic disease stages exhibit general differences in the interaction with entry receptors. We included members of all types of inhibitors currently identified: (i) agents that block gp120 binding to CD4 (CD4-IgG 2 and monoclonal antibody [MAb] IgG 1 b12), (ii) compounds that block the interaction with CCR5 (the chemokine RANTES/CCL5, the smallmolecule inhibitor AD101, and the anti-CCR5 antibody PRO 140), (iii) the fusion inhibitor enfuvirtide (T-20), and (iv) neutralizing antibodies directed against gp120 (MAb 2G12) and gp41 (MAbs 2F5 and 4E10). No differences between viruses from acute and chronic infections in the susceptibility to inhibitors targeting the CD4 binding site, CCR5, or fusion or to MAb 2G12 were apparent, rendering treatment with entry inhibitors feasible across disease stages. The notable exceptions were antibodies 2F5 and 4E10, which were more potent in inhibiting viruses from acute infection (P ‫؍‬ 0.0088 and 0.0005, respectively), although epitopes of these MAbs were equally well preserved in both groups. Activities of these MAbs correlated significantly with each other, suggesting that common features of the viral envelope modulate their potencies.Therapy of human immunodeficiency virus type 1 (HIV-1) infection with a combination of antiretrovirals inhibiting the viral enzymes reverse transcriptase and protease can significantly decrease HIV-related morbidity and mortality (49, 62). However, due to the toxicity of these drugs and the emergence of resistant viral variants, alternative treatment strategies are urgently needed (31,33,36). Entry of HIV-1 into target cells requires expression of the receptor CD4 and a fusion coreceptor, most commonly the chemokine receptors CCR5 and CXCR4 (19,66). The entry process proceeds via a cascade of events that provide multiple opportunities for therapeutic intervention, and several agents targeting this process have been developed over recent years. Considerable effort has been put into investigating the interaction of the virus with its entry receptors and the identification of potential antiretrovirals (66). Neutralizing antibodies were among the first agents identified which block viral entry. Direct antiviral activity is attributed to antibodies directed against specific epitopes on the envelope glycoproteins gp120 and gp41, which inhibit viral entry by blocking virion attachment to its receptors or membrane fusion (65). During natural infection the effect of the autologous neutralization response appears to be limited, since the virus rapidly escapes the immune pressure in most individuals (14,15,54,55,67,76,101). Nevertheless, rare potent monoclonal antibodies (MAbs) with broad activity have been isolated from infected individuals. These antibodies define four neutralization-sensitive epitopes within gp120 and gp41; they are characterized by the MAbs IgG 1 b12 (5,...

While certain antibodies directed against the human immunodeficiency virus (HIV) envelope have the potential to suppress virus replication in vitro, the impact of neutralizing antibodies in vivo remains unclear. In a recent proof-of-concept study, the broadly neutralizing monoclonal antibodies 2G12, 4E10, and 2F5 exhibited inhibitory activities in vivo, as exemplified by a delay of the viral rebound following the interruption of antiretroviral therapy. Unexpectedly, the antiviral effect seen was most prominently due to 2G12 activity. To further investigate whether differential HIV-inhibitory activity was due to different pharmacokinetic properties of the antibodies, we performed a formal pharmacokinetic analysis with 14 patients. Repeated infusions at high dose levels were well tolerated by the patients and did not elicit an endogenous immune response against the monoclonal antibodies. ؎ 1.1 days). The comprehensive pharmacokinetic data from this long-term multiple-dose phase II study were coherent with those from previous short-term phase I studies, as assessed by compartmental and noncompartmental techniques. The anti-HIV type 1 antibodies studied showed distribution and elimination kinetics similar to those seen for other humanlike antibodies. Further studies examining tissue concentrations to explain the differential in vivo activity of the anti-gp120 antibody compared with those of the two anti-gp41 antibodies are warranted.

Acquisition of leptospirosis during recreational activities also occurs in resource rich countries and might be even more common than occupational acquisition; diagnosis seems to be frequently missed due to the disease's multifaceted clinical presentation and insufficient awareness of caregivers.

Acute HIV-infection mostly presents with unspecifc symptoms. Thus the acute retroviral syndrome is often not readily recognized. Here we present an interim analysis of a prospective study from 62 patients with documented acute HIV infection acquired between January 2002-August 2004 in the greater Zurich area. 61.5% of patients were infected by homosexual contacts, mostly with HIV-1 subtype B, 34% acquired infection by heterosexual contacts, often with non-B-virus subtypes. Transmission occurred in all sexually active age groups (18-72 years). Clinical symptoms presented as follows: fever (77%), pharyngitis (56%), fatigue (52%), gastrointestinal symptoms (45%), rash (39%). On first physician contact, an ARS was only suspected in 27% of the cases. Patients primarily called on their family doctors (37.5%), went to see larger walk in clinics or emergency rooms (37.5%), and 16% were hospitalised. In 16% of patients other sexually transmitted diseases were diagnosed contemporaneously. Drug resistant virus (single class resistance) was transmitted in only one patient.