Memory T cells do not recognise circulating HIV in late infection

In patients with advanced-stage HIV infection, virus-specific CD8 T cells no longer effectively recognise autologous virus, even though they continue to respond to a laboratory-adapted strain of HIV, investigators at Harvard Medical School report.

This may explain why AIDS patients can no longer control viral replication, Dr Sang Kyung Lee and associates suggest in the 1 November issue of the Journal of Clinical Investigation.

Moreover, they write: “Conventional assays that measure responses to consensus sequences from lab-strain viruses may overestimate the breadth and diversity of functioning virus-specific CD8 T cells in vivo.”

The Boston-based researchers examined the CD8 T cell response of 11 HIV-infected subjects; five were asymptomatic (Stage A), three were exhibiting minor symptoms (Stage B) and three had major opportunistic infections (Stage C). For the analysis, the authors infected primary CD4 T cell targets with virus isolated from each patient or with the HIV lab strain IIIB.

“By using cells as targets, we have a more physiological test of CD8 cell response than in typical lab tests, where they are just testing cell response to common viral gene segments,” co-author Dr Premlata Shankar explained.

The magnitude of the functional response, as measured by the number of CD8 cells producing interferon (IFN)-gamma when they were incubated with the infected CD4 cells, declined with disease progression. The frequency of IFN-gamma producing cells was even lower in response to cells infected with autologous virus versus those infected with HIV-IIIB.

The research team also characterised the clonotypic composition of responding cells. The results showed that in two of three Stage A subjects, the T cell receptor clonotypes against the two different viral strains overlapped a great deal; clonotypes exclusive to one virus or the other made up less than 10% of the response.

However, in one other Stage A patient, three Stage B patients and two Stage C patients, the dominant T cell receptor clonotypes did not overlap at all. “Consequently, HIV-IIIB-responding cells do not recognise autologous virus and vice versa in symptomatic patients,” the authors state.

They suggest that the CD8 T cells that are generated early in infection persist “even after viral mutations make them irrelevant.” During late infection, the ability of CD8 cells to respond to new epitopes presented by viral mutants is apparently impaired because of CD4 T helper cell deficiency and cytokine imbalance, they add.

The investigators stress the need to develop assays that do not overstate a patient’s functional response to autologous virus.

“AIDS is a very complex disease,” Dr Shankar noted, so the phenomena they observed are “probably not the only reason” that patients lose the ability to control viral replication. “But it is an important reason,” she emphasised.

She said that it will be important to see the results of longitudinal studies her team is planning in which patients’ CD8 T cells’ responsiveness to autologous HIV will be examined.

Lee SK, Xu Z, Lieberman J, Shankar P. The functional CD8 T cell response to HIV becomes type-specific in progressive disease. J Clin Invest 2002 Nov;110(9):1339-47