Anti-CCR5 monoclonal antibody, clone HEK/1/85a [R-PE]

Objectives: To construct a classifier that predicts the probability of viral control after analytical treatment interruptions (ATI) in HIV research trials. Methods: Participants of a dendritic cell-based therapeutic vaccine trial (DCV2) constituted the derivation cohort. One of the primary endpoints of DCV2 was the drop of viral load (VL) set point after 12 weeks of ATI (delta VL12). We classified cases as "controllers" (delta VL12 > 1 log10 copies/mL, n = 12) or "noncontrollers" (delta VL12 < 0.5 log10 copies/mL, n = 10) and compared 190 variables (clinical data, lymphocyte subsets, inflammatory markers, viral reservoir, ELISPOT, and lymphoproliferative responses) between the 2 groups. Naive Bayes classifiers were built from combinations of significant variables. The best model was subsequently validated on an independent cohort. Results: Controllers had significantly higher pre-antiretroviral treatment VL [110,250 (IQR 71,968-275,750) vs. 28,600 (IQR 18737-39365) copies/mL, P = 0.003] and significantly lower proportion of some T-lymphocyte subsets than noncontrollers: prevaccination CD4(+)CD45RA+RO+ (1.72% vs. 7.47%, P = 0.036), CD8(+)CD45RA+RO+ (7.92% vs. 15.69%, P = 0.017), CD4+CCR5+ (4.25% vs. 7.40%, P = 0.011), and CD8+CCR5+ (14.53% vs. 27.30%, P = 0.043), and postvaccination CD4+CXCR4+ (12.44% vs. 22.80%, P = 0.021). The classifier based on pre-antiretroviral treatment VL and prevaccine CD8(+)CD45RA+RO+ T cells was the best predictive model (overall accuracy: 91%). In an independent validation cohort of 107 ATI episodes, the model correctly identified nonresponders (negative predictive value = 94%), while it failed to identify responders (positive predictive value = 20%). Conclusions: Our simple classifier could correctly classify those patients with low probability of control of VL after ATI. These data could be helpful for HIV research trial design.

Objective: Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. Design: Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. Methods: First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. Results: PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. Conclusion: Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.