BACKGROUND

In the PEPI-Malawi trial, infants received up to 14 weeks of extended nevirapine (NVP) or extended NVP plus zidovudine (NVP+ZDV) to prevent postnatal HIV transmission. We examined emergence and persistence of NVP resistance in HIV-infected infants who received these regimens prior to HIV diagnosis.

METHODS

Infant plasma samples collected at 14 weeks of age were tested using the ViroSeq HIV Genotyping System and a sensitive point-mutation assay, LigAmp (for K103N and Y181C). Samples collected at 6 and 12 months of age were analyzed using LigAmp.

RESULTS

At 14 weeks of age, NVP resistance was detected in samples from 82 (75.9%) of 108 HIV-infected infants. While the frequency of NVP resistance detected by ViroSeq was lower in the extended NVP+ZDV arm than in the extended NVP arm, the difference was not statistically significant (38/55=69.1% vs. 44/53=83.0%, P=0.12). Similar results were obtained using LigAmp. Using LigAmp, the proportion of infants who still had detectable NVP resistance at 6 and 12 months was similar among infants in the two study arms (at 6 months: 17/20=85.0% for extended NVP vs. 21/26=80.8% for extended NVP+ZDV, P=1.00; at 12 months: 9/16=56.3% for extended NVP vs.10/13=76.9% for extended NVP+ZDV, P=0.43).

CONCLUSIONS

Infants exposed to extended NVP or extended NVP+ZDV had high rates of NVP resistance at 14 weeks of age, and resistant variants frequently persisted for 6–12 months. Frequency and persistence of NVP resistance did not differ significantly among infants who received extended NVP only vs. extended NVP+ZDV prophylaxis.

Purpose

The neuropeptide, alpha-melanocyte stimulating hormone (α-MSH), is an endogenous antagonist of inflammation. Injections of α-MSH peptide into inflamed tissues have been found to be very effective in suppressing autoimmune and endotoxin mediated diseases. We evaluated the potential to suppress ocular autoimmune disease (uveitis) by augmenting the expression of α-MSH through subconjunctival injections of naked adrenocorticotropic hormone amino acids 1-17 (ACTH1-17) plasmid.

Methods

We clinically scored the uveitis over time in B10.RIII, C57BL/6, and melanocortin 5 receptor knock-out (MC5r(-/-)) mice with experimental autoimmune uveitis (EAU) that were conjunctively injected with a naked DNA plasmid encoding ACTH1-17 at the time of EAU onset and three days later. The post-EAU retina histology of plasmid injected eyes was examined, and post-EAU concentrations of α-MSH in aqueous humor was assayed by ELISA.

Results

The subconjunctival injection of ACTH1-17 plasmid augmented the concentration of α-MSH in the aqueous humor of all post-EAU mice. The injection of ACTH1-17 suppressed the severity of EAU in the B10.RIII and C57BL/6 mice but the MC5r(-/-) mice. In all the models of EAU, the ACTH1-17 injection helped to preserve the structural integrity of the retina; however, post-EAU aqueous humor was not immunosuppressive.

Conclusions

The subconjunctival injection of the α-MSH expression vector ACTH1-17 plasmid is effective in suppressing EAU. The suppressive activity is dependent on MC5r expression, and possibly works though α-MSH antagonism of inflammation than on α-MSH directly modulating immune cells. The results suggest that an effective therapy for uveitis could include a gene therapy approach based on delivering α-MSH.