Research ArticleHIV

AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

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Science Translational Medicine  24 Jul 2019:
Vol. 11, Issue 502, eaau5409
DOI: 10.1126/scitranslmed.aau5409

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Stepping up protection against SIV

HIV and the related simian immunodeficiency virus (SIV) enter cells through the CD4 receptor, so therapeutics have been designed based on CD4 to prevent viral binding and cell entry. Gardner et al. tested the ability of a modified CD4 protein to protect against a stringent SIV challenge. The protein, rh-eCD4-IgI39N, was delivered to nonhuman primates with an adeno-associated virus vector before repeated escalated SIVmac239 challenges. All control animals quickly became infected, but much higher doses were needed to infect rh-eCD4-IgI39N–treated animals. Subsequent analysis revealed that viral loads in the treated group were lower and that rh-eCD4-IgI39N puts selective pressure on SIV. Their results show that gene therapy with CD4-based proteins could protect against HIV infection.

Abstract

A number of simian and simian human immunodeficiency viruses (SIV and SHIV, respectively) have been used to assess the efficacy of HIV-1 vaccine strategies. Among these, SIVmac239 is considered among the most stringent because, unlike SHIV models, its full genome has coevolved in its macaque host and its tier 3 envelope glycoprotein (Env) is exceptionally hard to neutralize. Here, we investigated the ability of eCD4-Ig, an antibody-like entry inhibitor that emulates the HIV-1 and SIV receptor and coreceptor, to prevent SIVmac239 infection. We show that rh-eCD4-IgI39N expressed by recombinant adeno-associated virus (AAV) vectors afforded four rhesus macaques complete protection from high-dose SIVmac239 challenges that infected all eight control macaques. However, rh-eCD4-IgI39N–expressing macaques eventually succumbed to serial escalating challenge doses that were 2, 8, 16, and 32 times the challenge doses that infected the control animals. Despite receiving greater challenge doses, these macaques had significantly lower peak and postpeak viral loads than the control group. Virus isolated from three of four macaques showed evidence of strong immune pressure from rh-eCD4-IgI39N, with mutations located in the CD4-binding site, which, in one case, exploited a point-mutation difference between rh-eCD4-IgI39N and rhesus CD4. Other escape pathways associated with clear fitness costs to the virus. Our data report effective protection of rhesus macaques from SIVmac239.

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