Gorillas have been infected with the HERV-K (HML-2) endogenous retrovirus much more recently than humans and chimpanzees.

Human endogenous retrovirus-K (HERV-K) human mouse mammary tumor virus-like 2 (HML-2) is the most recently active endogenous retrovirus group in humans, and the only group with human-specific proviruses. HML-2 expression is associated with cancer and other diseases, but extensive searches have failed to reveal any replication-competent proviruses in humans. However, HML-2 proviruses are found throughout the catarrhine primates, and it is possible that they continue to infect some species today. To investigate this possibility, we searched for gorilla-specific HML-2 elements using both in silico data mining and targeted deep-sequencing approaches. We identified 150 gorilla-specific integrations, including 31 2-LTR proviruses. Many of these proviruses have identical LTRs, and are insertionally polymorphic, consistent with very recent integration. One identified provirus has full-length ORFs for all genes, and thus could potentially be replication-competent. We suggest that gorillas may still harbor infectious HML-2 virus and could serve as a model for understanding retrovirus evolution and pathogenesis in humans.

Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.

Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies.

HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41's membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1-infected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design.