Analysis of cells from long term non-progressors points the way to using vaccines and STIs to restore immune response to HIV

10 April 2002. Related: Conference reports, CROI 9th (Retrovirus) 2002.

Graham McKerrow, HIV i-Base

Dr Brigitte Autran, one of the world’s leading researchers into immune reconstitution with highly active antiretroviral therapy (HAART), told the 9th Conference on Retroviruses and Opportunistic Infections of the ground-breaking research that she and colleagues are conducting at the Hôpital Pitié-Salpêtrière in Paris [1].

She summarised current thinking on immune reconstitution and suggested how immunity to HIV might be enhanced so as to improve the treatment and control of infection.

Dr Autran, a professor at the University of Paris, observed that it is widely accepted that HAART, when initiated during chronic infection, leads to the restoration of both naïve and memory CD4+ and CD8+ T-cells. Nevertheless, immunity to HIV is not usually restored even with prolonged fully suppressive HAART. HIV-specific CD4+ T cells are lost early in infection and HIV-specific CTLs (cytotoxic lymphocytes) are not generated or are less effective because of the loss of CD4+ T cell help and – as a result of antiretroviral therapy – low levels of HIV antigen.

However, there is an exception to this: when therapy is started during acute infection HIV-specific CD4+ T cells are preserved and the development of HIV-specific CTLs is delayed, but they are still capable of responding.

“The most important thing is not only to reconstitute the numbers of cells but, obviously, to reconstitute the defences of the patient against opportunistic pathogens and against HIV itself,” Dr Autran told delegates. The reconstitution of the host’s defences during antiretroviral therapy (ART) is antigen-driven. With opportunistic pathogens, the load and antigen production is not directly influenced by HAART, she said, whereas HIV load and antigen production are reduced by HAART.

Dr Autran was one of the first scientists to describe the process of immune reconstitution with HAART [2]. She told a plenary of the Seattle conference: “What we can call a suppressive HAART, although we know it is not completely suppressive, has several drawbacks in the context of HIV-specific immunity mediated by CTLs; and if it is introduced in chronic infection it will reduce the levels of pre-existing CTLs.”

“Concerning HIV-specific CD4+ cells: if the treatment is introduced at the time of primary infection it is good for the system, it is preserving the number and function of these HIV-specific CD4+ cells. But when it is introduced at time of chronic infection the low level of HIV antigens will not be able to restimulate appropriate CD4+ cells against HIV and it will prevent their restoration.”

“So it is considered that the major factor responsible for these abnormalities in reconstitution is reduced exposure to HIV, despite — we know it is persisting — some viral replication in many tissues.”

“It is probable, also, that an inappropriate presentation of HIV antigens due to persistent alteration in the network of dendritic cells might play a role. But obviously the amount of antigen produced might represent a major factor limiting reconstitution of immunity.”

“So it became clear that we could very simply restimulate the immune system simply by re-presenting HIV antigens to the T cells and the simplest way to do that was to interrupt the treatment.”

Dr Autran said that a few years ago treatment holidays “seemed to work, a little bit at least” so more research was devoted to analysing the implications.

“We concluded that indeed it is feasible to boost immunity with structured treatment interruptions but, at least in the context of chronic infection, it might be extraordinarily difficult to maintain a good equilibrium between the numbers of HIV-specific CD8+ and CD4+ cells and the virus; while, perhaps, in the context of primary infection… it might be easier to restimulate appropriate T cell response to the virus, capable to control the virus and maintain a long time off therapy.”

“So we were looking for other strategies to restimulate the immune system and we felt that perhaps the virus itself could be aprogenic [immuno-stimulating] and that we should use some therapeutic immunisation programmes to restimulate the T cells while the patient was still on therapy and before interrupting the treatment.”

So, ‘suppressive’ HAART delays HIV-specific CTL in primary infection, and reduces pre-existing CTLs in chronic infection. It also preserves HIV-specific CD4+ T cells in primary infection and prevents their restoration in chronic stages. There is reduced exposure to HIV despite persistent minimal virus replication, and inappropriate exposure to HIV antigens is due to persistent alterations of dendritic cell defects.

The Paris researchers followed a cohort of 70 long-term non-progressors (LTNPs) for five years, evaluating viral and host factors and comparing them with other chronically infected individuals [3].

Dr Autran said: “We concluded that the CD4+ T helper 1 responses, as characterised both by their capacity to produce interferon gamma and also by their numbers of cells producing interferon gamma negatively correlates with the plasma HIV and the provirus HIV and this is independently of the CD4+ counts and of any genetic factors. In summary, it is not because those patients are genetically protected against virus replication that their CD4+ cells are also protected and it appears that those cells might play a direct, active control on virus replication.”

“The new thing,” she added, “is that antibodies might also play a role in the control of established infections.” The researchers measured the levels of antibodies and measured the isotypes in immunoglobulins, particularly IgG1 and IgG2 against any pathogens. Analysis found high levels of IgG2 in LTNPs only. IgG2 directed against gag and gp41 antigens depended on Th1 rather than Th2 function CD4+ cells.

It was found that the level in the plasma of the IgG2 directed against gag and gp41 was negatively associated with HIV viral load. Multivariate analysis found that only the combination of the Th1 response measured by the numbers and the IgG2 phenotype was significantly correlated to the maintenance of the LTNP status.

Dr Autran reported: “IgG2 against gp41 was associated with 100% capacity to remain LTNPing while having low Elispot response despite IgG2 [being] associated with a poor maintenance of the LTNP status. So, obviously this Th1 function is extremely important in the control of the virus.”

She said that the goal of therapeutic vaccination strategies should be that when used to treat people with either primary or chronic infection, they should boost immunity to HIV while people are on treatment and provide strong immunity to the virus when treatment is interrupted by controlling virus replication and thus prolonging the time the patient can be off therapy.

Several clinical trials in France and elsewhere in Europe have been started in the last three years to investigate safe, well tolerated therapeutic vaccines, Dr Autran reported. The French investigators are using canary pox virus, which is recombinant for gag, envelope, protease and part of the RT and Nef gene. They can stimulate both specific CTL and CD4+ T cells. Trials are looking at the use of canary pox alone in chronic infection, canary pox plus lipopetides plus IL-2 in chronic and primary infections, and VCP plus inactivated virus in primary infection. The methods used in the trials are the same: once the patients are undergoing HAART they have several immunisations followed by therapeutic interruptions.

Dr Autran said: “Inactivated virus particles will also be able to play a role by activating the Th1 cells, and perhaps, by a complex mechanism, activate CTLs.”

None of the trials have yet finished but Dr Autran reported “very encouraging” intermediary results in terms of immunogenicity. “We know that these vaccine approaches are truly capable of inducing strong CD4+ T cell responses of the Th1 phenotype directed against the various antigens present in the vaccines. The CD8+ cells are currently being evaluated and we are now designing new trials involving new vaccines for the coming years and this is done in the context of a huge international effort.”

References:

1. Autran B. Immune reconstitution and immunologic responses to antiretroviral therapies: implications for therapeutic strategies. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Washington. Abstract L3.
2. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277:112-116.
3. Condotti D, Costagliola D, Joberty C, et al. Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with viral replication properties and cell tropism. French ALT Study Group. J Med Virol. 1999;58:256-263.