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Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1.

ABSTRACT: To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR using primers capable of distinguishing HIV-1(IIIB), HIV-1(SF2), and HIV-1(DH12) from one another; and serologic assays to monitor changes in binding and neutralizing antibodies. In contrast to an HIV-1-naive chimpanzee that rapidly became infected following the inoculation of HIV-1(DH12), the two chimpanzees previously infected with HIV-1(IIIB) resisted repeated and escalating inoculations of HIV-1(DH12), as monitored by virus isolation and PCR. The two animals previously infected with HIV-1(SF2) became infected with HIV-1(DH12) but in contrast to the case with the HIV-1-naive chimpanzee, no cell-free viral RNA was detected in the plasma by the branched DNA procedure and levels of peripheral blood mononuclear cell-associated viral DNA were reduced 35- to 50-fold.

SUBMITTER: Shibata R

PROVIDER: S-EPMC190369 | biostudies-other | 1996 Jul

REPOSITORIES: biostudies-other

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Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1.

Shibata R R Siemon C C Cho M W MW Arthur L O LO Nigida S M SM Matthews T T Sawyer L A LA Schultz A A Murthy K K KK Israel Z Z Javadian A A Frost P P Kennedy R C RC Lane H C HC Martin M A MA

Journal of virology 19960701 7

To test whether the protective effects of attenuated simian immunodeficiency virus vaccines in macaques were applicable to the human immunodeficiency virus type 1 (HIV-1)-chimpanzee system, two groups of animals, previously infected with HIV-1(IIIB) or HIV-1(SF2) were each challenged with a heterologous clade B virus, HIV-1(DH12). Following challenge, the parameters measured included virus isolation (from plasma, peripheral blood mononuclear cells, and lymph node tissue); quantitative DNA PCR us ...[more]

PMID: 8676459

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Project description:Chimpanzees in west central Africa (Pan troglodytes troglodytes) are endemically infected with simian immunodeficiency viruses (SIVcpzPtt) that have crossed the species barrier to humans and gorillas on at least five occasions, generating pandemic and nonpandemic forms of human immunodeficiency virus type 1 (HIV-1) as well as gorilla SIV (SIVgor). Chimpanzees in east Africa (Pan troglodytes schweinfurthii) are also infected with SIVcpz; however, their viruses (SIVcpzPts) have never been found in humans. To examine whether this is due to a paucity of natural infections, we used noninvasive methods to screen wild-living eastern chimpanzees in the Democratic Republic of the Congo (DRC), Uganda, and Rwanda. We also screened bonobos (Pan paniscus) in the DRC, a species not previously tested for SIV in the wild. Fecal samples (n = 3,108) were collected at 50 field sites, tested for species and subspecies origin, and screened for SIVcpz antibodies and nucleic acids. Of 2,565 samples from eastern chimpanzees, 323 were antibody positive and 92 contained viral RNA. The antibody-positive samples represented 76 individuals from 19 field sites, all sampled north of the Congo River in an area spanning 250,000 km(2). In this region, SIVcpzPts was common and widespread, with seven field sites exhibiting infection rates of 30% or greater. The overall prevalence of SIVcpzPts infection was 13.4% (95% confidence interval, 10.7% to 16.5%). In contrast, none of the 543 bonobo samples from six sites was antibody positive. All newly identified SIVcpzPts strains clustered in strict accordance to their subspecies origin; however, they exhibited considerable genetic diversity, especially in protein domains known to be under strong host selection pressure. Thus, the absence of SIVcpzPts zoonoses cannot be explained by an insufficient primate reservoir. Instead, greater adaptive hurdles may have prevented the successful colonization of humans by P. t. schweinfurthii viruses.

Project description:Comprehensive assessments of immune correlates of protection in human immunodeficiency virus (HIV) vaccine trials are essential to vaccine design. Neutralization sieve analysis compares the neutralization sensitivity of the breakthrough transmitted/founder (TF) viruses from vaccinated and control animals to infer the molecular mechanisms of vaccine protection. Here, we report a robust neutralization sieve effect in a nonhuman primate simian immunodeficiency virus (SIV) vaccine trial (DNA prime/recombinant adenovirus type 5 [rAd5] boost) (VRC-10-332) that demonstrated substantial protective efficacy and revealed a genetic signature of neutralization resistance in the C1 region of env. We found significant enrichment for neutralization resistance in the vaccine compared to control breakthrough TF viruses when tested with plasma from vaccinated study animals, plasma from chronically SIV-infected animals, and a panel of SIV-specific monoclonal antibodies targeting six discrete Env epitopes (P < 0.008 for all comparisons). Neutralization resistance was significantly associated with the previously identified genetic signature of resistance (P < 0.0001), and together, the results identify virus neutralization as a correlate of protection. These findings further demonstrate the in vivo relevance of our previous in vitro analyses of the SIVsmE660 challenge stock, which revealed a broad range of neutralization sensitivities of its component viruses. In sum, this report demonstrates proof-of-concept that phenotypic sieve analyses can elucidate mechanistic correlates of immune protection following vaccination and raises a cautionary note for SIV and SHIV (simian-human immunodeficiency virus) vaccine studies that employ challenge strains with envelope glycoproteins that fail to exhibit neutralization resistance profiles typical of TF viruses.With more than 2 million new infections annually, the development of an effective vaccine against HIV-1 is a global health priority. Understanding immunologic correlates of protection generated in vaccine trials is critical to advance vaccine development. Here, we assessed the role of vaccine-elicited neutralizing antibodies in a recent nonhuman primate study of a vaccine that showed significant protection against simian immunodeficiency virus (SIV) challenge and suggested a genetic signature of neutralization sensitivity. We found that breakthrough viruses able to establish infection in vaccinated animals were substantially more resistant to antibody-mediated neutralization than were viruses from controls. These findings suggest that vaccine-elicited neutralizing antibodies selectively blocked the transmission of more sensitive challenge viruses. Sieve analysis also corroborated a genetic signature of neutralization sensitivity and highlighted the impact of challenge swarm diversity. Our findings suggest an important role for neutralization sieve analyses as an informative component of comprehensive immune-correlates analyses.

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Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1.

Publications

Resistance of previously infected chimpanzees to successive challenges with a heterologous intraclade B strain of human immunodeficiency virus type 1.

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