Molecular Biology Of Retroviruses Associated With AIDS

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

HIV is unable to establish infections in macaque monkeys. We previously reported that an HIV-1 derivative, designated HIV 1NL-DT5R, containing a 7 amino acid segment from SIV CA and the entire SIV vif gene was able to initiate spreading infections in cultured macaque PBMC whereas wild type HIV-1 could not. Those experiments indicated that the presence of 666 SIV nucleotide sequences (6.7%) at these two specific locations within the full-length 9894 nucleotide HIV-1 genome was sufficient to counteract innate restriction factors residing in simian cells such as APOBEC3 and TRIM5alpha family members, which otherwise block HIV-1 replication. These results have now been extended to the organismal level by showing that HIV 1NL-DT5R, which is more than 93% HIV, was able to establish infections in all 5 pig-tailed macaques inoculated and elicited humoral responses against all of the HIV-1 structural proteins using commercially available Western blotting strips.[unreadable] [unreadable] In other studies, we have continued investigations of CCR5-utilizing SHIVs that are able to consistently replicate to high titers in inoculated macaques and cause immunodeficiency in a timely manner. Our approach has been to serially passage such R5 SHIV candidates animal-to-animal and introduce genetic changes associated with augmented replicative properties into the starting molecularly cloned virus. Presently we have generated R5 SHIVs exhibiting peak plasma viremia levels reaching 7 to 8 logs of viral RNA copies/ml and set points of 4 logs of viral RNA copies/ml. In most cases, memory CD4+ T lymphocytes are exclusively targeted for infection and depletion. These R5 SHIVs can be used in vaccine experiments in which efficacy is measured from virus load determinations.