GENEVA--Highly active antiretroviral therapy (HAART), usually including a protease inhibitor, can suppress human immunodeficiency virus (HIV) so much that the immune system actually begins to heal, according to work presented at the 12th World Conference on AIDS. In patients who respond well to HAART, CD4+ and CD8+ cell counts move toward normal, and the risk of opportunistic infections decreases (see Oncology News International, August, 1998, pp 1 and 20).
The missing piece of this picture is the most important one: Even when HAART knocks the virus back to undetectable levels, the HIV-specific T-cell response does not recover.
Whether the new circulating T cells are completely functional is also unclear, but immune reconstitution includes some normalization of the distribution of naïve and memory T cells and some improvements in T-cell functions.
It does not, unfortunately, include an upsurge in cellular immunity directed against HIV, such as an increase in cytotoxic T lymphocytes (CTLs), and although many adult patients have a resurgence of naïve CD4+ T cells with use of HAART, there is no clear evidence that enough of these cells are being made for true immune restoration.
One optimistic note at this conference was a report that HAART can enable production of new naïve T cells in children with HIV, apparently related to the presence of a functional thymus.
Researchers have been examining two possible scenarios in immune reconstitution after effective suppression of HIV. One is that HIV-specific T-cell responses would decrease because patients with low viral loads would also have less HIV antigen to stimulate immunity. The other is that HIV-specific immune responses might increase because the immune suppression caused by the virus would decrease as the viral load dropped. There is evidence that both may happen, at different times and in different patients.
T-cell receptors on CD4+ and CD8+ T cells can be expressed in many ways, which enables T cells to recognize many different antigens in normal subjects. The T-cell repertoire in HIV-positive patients becomes skewed. This is caused by expansion of T cells expressing particular T-cell receptors. AIDS specialists have hoped that aggressive treatment with HAART would stop this process and help maintain the more diverse T-cell receptor repertoire needed for adequate immune function.
Hugo Soudeyns, PhD, of the Laboratory of AIDS Immunopathogenesis, Lausanne, Switzerland, reported that this immune stabilization may indeed be occurring, at least with CD8+ T cells. Dr. Soudeyns used a heteroduplex mobility assay to measure oligoclonal expansions of various T-cell receptor V beta families in two patients treated with HAART. This was done using imaging densitometry of gels of the T-cell receptor beta chain.
After 28 and 35 weeks of follow-up, respectively, in the two patients, both of whom had responded to HAART, Dr. Soudeyns observed that the number of expanded oligoclonal populations was reduced. This reduction would be expected to result in a more normal spread of T-cell responsiveness. "The main issue is, what are these clones recognizing in terms of antigen?" he said. "The rapid stabilization of the T-cell receptor repertoire seen in treated patients may prevent the clonal exhaustion of HIV-specific CTL clones observed in untreated subjects."
In related work, Guy Gorochov, MD, of Hôpital de la Pitie, Paris, also observed that effective HAART suppression of viral activity could cause "impressive stabilization of the CD8 repertoire during the second 6 months of treatment," and a return to near-normal polyclonal CD8 T-cell receptors with continued therapy.
However, Dr. Gorochov also warned that if HIV replication is not fully controlled, the pretreatment oligoclonal state persists, apparently because active replication is the driving force behind the dramatic clonal expansion of CD8 cells seen in untreated HIV infection.
Charles Rinaldo, PhD, of the University of Pittsburgh, looked specifically at what happens to memory CTLs after HAART. He studied 27 late-stage adult patients with CD4 counts under 200
cells/mm3 and plasma loads over 220,000 copies/mL at baseline. Dr. Rinaldo said that prolonged suppression of HIV with indinavir(Drug information on indinavir) (Crixivan)/zidovudine (AZT, Retrovir)/lamiduvine (3TC, Epivir) produces a "profound but incomplete enhancement" of anti-HIV CTL activity.
Enhancing CTL Precursors
He found that CTL precursors of memory T cells increased over the full first year of treatment but still had only a minimal response to the HIV gag protein. The numbers of these important precursor cells dropped back to baseline after 2 years.
Dr. Rinaldo suggested that this unfortunate change "may be a normal homeostatic response to low viral load." He is now trying an end run around this homeostatic mechanism by providing ongoing but benign stimulation with an HIV protein. He is enhancing the production of HIV-specific CTL precursors by growing large numbers of dendritic cells in vitro, stuffing them with cationic liposomes containing an HIV protein, and adding them to cultures of T cells.
He has found that the CTL response can be recovered by repeated treatment with the HIV-protein-containing dendritic cells, particularly if IL-12 is also added to the culture. This is all in vitro work so far, but does suggest a possible strategy for filling in the most important piece missing from immune recovery after HAART--the generation of CTLs able to kill HIV-infected cells.
Ann-Charlotte Leandersson, BSc, at the Swedish Institute for Infectious Disease Control, Stockholm, presented elegant but depressing data confirming that "successful HAART therapy does not induce recovery of HIV-specific CD4+ responses" once they have been lost in adult patients. "No or very low increases in HIV-specific T-cell responses were seen even though viral load was reduced and CD4 levels increased," she reported.
Dr. Leanderssons group attempted to restore HIV-specific immunity by vaccinating patients with a recombinant gp160 vaccine prior to treatment with HAART, and did observe "a tendency toward higher response in patients who had received vaccination prior to HAART." This again suggests that some type of vaccination strategy may be needed for immune restoration.
Hopeful News in Children
The situation in children may be different, since they still have functional thymus glands. Allessandra Vigano, MD, of the University of Milan, reported that the all-important naïve CD4+ T cells do increase after HAART treatment, even in children with advanced disease.
Thymus volume also increased, and there was a positive correlation between thymus volume (as measured by MRI) and the increase in CD4 cells, the ratio of naïve to memory cells, and the expansion of the T-cell receptor beta repertoire. Most patients also had increased ability to respond to recall antigens.