Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: Association with disease progression and influence of immune pressure

Abstract

Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n=120) or chronic (n=207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r=0.19, p=0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p=0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r=−0.21, p=0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course.

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

“…More recently, a study of Ͼ100 clinical isolates showed that subtype D had higher Pol-driven replication capacity than subtype A and directly linked these differences to faster disease progression in the former than in the latter subtype (35). Furthermore, we recently demonstrated subtype-specific differ-ences in Nef function (36) and showed that Nef functional differences in acute infection correlate with markers of disease progression (37). Taken together, these results support subtype-specific differences in HIV-1 protein function as determinants of disease progression.…”

Human Immunodeficiency Virus infection and cardiovascular disease

“…HIV-1 contains a singlestranded RNA genome that is 9 kilobases in length and contains 9 genes that encode 15 different proteins (Mann et al, 2014). The major viral proteins (some of which contain >1 protein subunit) are classified as structural proteins (Gag, Pol, and Env), regulatory proteins (Tat and Rev), and accessory proteins (Vpu, Vpr, Vif, and Nef) (Greenway et al, 2002).HIV infection of a host cell begins with the binding of the virus particle (virion) to the host cell.…”

“…Gag then functions in the budding of mature virions from the plasma membrane. The Nef protein acts on the cellular environment to promote replication by inhibiting the host immunologic response to HIV and inhibiting death of infected cells by apoptosis (Mann et al, 2014). (Mann et al, 2014).…”

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

“…3C) for how the Loc-103275158 protein might combat Nef downregulation of MHC-I from the surface of tarsier cells infected by an appropriate primate lentivirus, i.e., after the mechanism of HIV-1 Nef in humans. 5,7,[19][20][21] Theoretically, a phosphorylation/dephosphorylation event within the CD loop would occur when the protein is in a "closed" conformation; based upon our modeled contacts, we prefer the notion that the MHC-I CD initially associates with some affinity to this closed conformation (left cartoon, Fig. 3C).…”