Host protein p21 restricted HIV progression in elite-controllers

VANCOUVER — The p21 host protein that inhibits HIV replication in hematopoietic stem cells appeared to restrict HIV infection in elite controllers. Manipulation of p21 may offer opportunities to increase hosts’ resistance to HIV infection, according to new findings presented by Mathias Lichterfeld, MD, PhD.

“This gene expression is much more strongly expressed in elite controllers,” Lichterfeld, instructor in medicine at Massachusetts General Hospital and Harvard Medical School, Boston, said during a press conference. “We do not fully understand why these certain patients have higher levels of the p21 protein, but this is something that is currently being investigated. If we were able to increase p21 expression in CD4 T cells in the broader population, we may then be able to increase resistance to HIV on a larger scale.”

Elite controllers, which represent 0.3%-1% of all HIV patients, according to Lichterfeld, have been described as a small population of HIV-infected patients who possess an HIV-positive antibody test but test negatively for viral load. Most elite controllers show no signs of disease progression, however, correlates of immune protection in this patient population are not well defined. For this reason, Lichterfeld and colleagues set out to examine how p21 transforms HIV replication in CD4 T cells among 15 elite-controllers, 14 HIV-negative patients, 16 HIV-progressors and 10 patients treated with HAART.

The researchers utilized PCR assays to measure HIV DNA and HIV mRNA. Next, p21 gene expression was assessed by RT-PCR and western blots in quiescent and activated CD4 T cells. Functional HIV infection assays were performed in the presence or absence of p21.

Compared with CD4 T cells from all other patient cohorts, CD4 T cells from elite-controllers were significantly less susceptible to HIV infection (P<.01). According to Lichterfeld, this resistance was due to less effective reverse transcription and HIV mRNA transcription from proviral DNA.

Moreover, defective viral replication in elite-controllers led to a 10- to 20-fold increased expression of p21 in CD4 T cells from elite controllers (P<.001). Barriers of p21 significantly enhanced reverse transcription and HIV mRNA transcription in CD4 T cells in ex-vivo infection assay (P=.01).

“These data show the CD4 T cells in elite-controllers are less susceptible to HIV infection when compared with other patients,” Lichterfeld said during a press conference. “There is some sort of resistance of CD4 T cells from elite-controllers to HIV, but not complete resistance. This could provide an alternative way to enhance resistance to HIV patients.” – by Jennifer Southall

For more information:

Lichterfeld. #819. Presented at: the IDSA 48th Annual Meeting; Oct. 21-24, 2010; Vancouver, B.C.