Ancient Retrovirus Uses 2 Mechanisms to Interfere with HIV Replication

Inhibiting particle release and infectivity could lead to a cure for HIV-1.

New findings provide insight into the mechanisms by which human endogenous retroviruses (HERV-K) group specific antigen (Gag) interferes with HIV-1 replication.

HERVs are remnants of ancient retroviral infections that constitute approximately 8% of human genomic DNA. Prior studies show that T cells create an immune response against HERVs in patients with HIV.

Scientists hypothesized that HERV expression can be caused by HIV infection, making HIV an easier target by focusing on the HERV antigens rather than the mutating HIV antigens. In a prior study, investigators from Kumamoto University showed a correlation between the coassembly of HIV-1 Gag and HERV-K Gag, and the reduced proliferation and infectivity of HIV-1.

In the current study published in Retrovirology, the authors sought to identify the mechanisms by which HERV-K gag interferes with HIV-Gag assembly and particle infectivity.

The investigators showed that the coexpression of HERV-K Gag with HIV-1 Gag changed the size and morphology of progeny HIV-1 particles and severely diminished infectivity.

To determine molecular determinants for coassembly specificity and inhibition of HIV-1 release efficiency and infectivity, the investigators further compared the chimeric constructs of HERV-K-MLV.

The results of the study showed that inference is caused by 2 distinct molecular mechanisms: the CA N-terminal domain (NTD) of HERV-K Gag is important for reduction of HIV-1 release and infectivity, but different regions within CA are involved in the effects on the HIV-1 release and infectivity.

“Interestingly, these regions of HERV-K Gag were not required for reduction of progeny HIV-1 infectivity,” the authors wrote. “In the current study, we showed that HERV-K Gag can suppress the HIV-1 assembly at an early stage and alter the properties of HIV-1 particles, via distinct molecular mechanisms. Altogether, endogenous retroviral elements are likely to have been contributing survival of the hosts in the evolutionary time scale via a wide variety of mechanisms.”

Although the findings show promise, the investigators stress that more research needs to be done.

“While we have found that release efficiency and infectivity of HIV-1 particles are hindered by HERV-K Gag, they appear to be products of 2 separate mechanisms,” said project leader Dr Kazuaki Monde. “HIV-1 particle release from cells that also express HERV-K Gag is reduced significantly but the specifics of how infectivity is also reduced still eludes us. Certainly, more research into HERV-K CA is needed to determine how it is able to reduce both particle release and infectivity of HIV-1.”