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Impact of Antiretroviral Therapy and Changes in Virus
Load on Human Immunodeficiency Virus
(HIV)Specific T Cell Responses in Primary HIV
Infection
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These study findings argue against initiating HAART during acute infection....Previous reports point to the potential advantage of initiating treatment very early, before seroconversion, to preserve or enhance HIV-specific T cell responses. It has been shown that some individuals who were treated early were able to control HIV replication, at least transiently, after HAART was interrupted......In our study, the time when the therapy was initiated did not influence the evolution of HIV-specific CD4+ or
CD8+ T cell responses, as indicated by the similar changes of these responses in groups of acute and early subjects......Previous data suggested the existence of very high proliferation indices when treatment was initiated in acute infection,
before seroconversion. However, in our study, changes in HIV-specific CD4+ T cell responses were moderate and identical in both groups of subjects......we did not find any increase in the breadth and magnitude of the HIV-specific CD8+ T cell responses in the group of early subjects, compared with that in the acute group.... the results provided here indicate that the hypothesis suggesting that only early treatment of HIV infection could preserve immune function can be moderated......the absence of any treatment or the incomplete virological control did not prevent the development of an HIV-specific CD4+ T cell response, which suggests that the latter is preserved at least through the first 18 months of infection......our data point to the fact that an early therapy aimed at preserving the HIV-specific immune response may not be necessary in all subjects and that some individuals could remain untreated for some period of time, thereby avoiding the problems of drug toxicity and viral resistance by lack of treatment adherence.
Summary- Virus-specific CD8+ and CD4+ T cell responses play a central role in the control of viral infections. During human immunodeficiency virus (HIV) primary infection (PI), the early dynamic between viral replication and the immune response is thought to influence the longitudinal pattern of virological and immunological markers, as well as the prognosis for clinical progression. This dynamic is altered by the early administration of highly active antiretroviral therapy (HAART). Indeed, treatment of HIV PI with HAART has a beneficial effect on laboratory markers of disease progression, as well as some beneficial clinical impact. However, despite the fact that undetectable levels of plasma HIV RNA can be rapidly achieved, HIV replication generally rebounds after cessation of therapy. Therefore, antiretroviral drug regimens have to be maintained to control viremia, and the potential benefits of early intervention are counterbalanced by treatment adherence and toxicity problems, such as metabolic abnormalities, including lipodystrophy. Therefore, it is very important to determine the most appropriate time to initiate HAART and,
particularly, to clarify whether initiating therapy at the time of acute PI is most beneficial.
Theoretical benefits of initiating therapy during acute PI are strengthening the cellular immune response and helping control viral replication. It has long been hypothesized that a severe depletion of HIV-specific CD4+ T cells occurs
during the earliest stage of infection, when they could be preferentially targeted by HIV for infection and destruction. This hypothesis was strengthened by the lack of restoration of HIV-specific CD4+ T cell responses under therapy
during chronic infection in one study. By contrast, in other studies, the immediate initiation of antiretroviral therapy during PI preserved or restored HIV-specific CD4+ T cell responses, which suggests that the destruction of these
specific T cells was prevented. Conversely, HAART generally leads to a decrease in HIV-specific CD8+ T cell responses that parallels the decrease in virus load.
To further evaluate the development of HIV-specific immune responses during PI and the impact of HAART, we collected data from the PRIMO observational study and explored concomitant changes in HIV-specific CD4+ and CD8+
T cell responses in a large cohort of subjects studied at the time of PI. We first examined the relationship between HIV-specific CD4+ and CD8+ T cell responses at the time of PI. We then performed a longitudinal follow-up to
determine the impact of HAART on these responses and their relationship with virus load by comparing the responses of both treated subjects who achieved complete or only partial virus suppression and untreated subjects. Finally, we
determined whether antiretroviral therapy had a different impact on cellular immune responses when initiated very early, before seroconversion, than when initiated slightly later, during the first 3 months of infection.
Human immunodeficiency virus (HIV) specific CD4+ and CD8+ T cell
responses were evaluated prospectively in a large cohort of subjects with HIV
primary infection via long-term follow-up examining different virological
profiles related to different treatment interventions. No correlation was
observed between baseline virus load and HIV-specific CD4+ and CD8+ T cell
responses. Highly active antiretroviral therapy (HAART)induced suppression
of viremia was associated with an increase in CD4+ T cell proliferative
responses. The HIV-specific proliferative response also increased, at least in
the first 18 months, in subjects with detectable viremia, either treated or
untreated. The magnitude of the HIV-specific CD8+ T cell response decreased
with suppression of viremia. In subjects with detectable viremia, the breadth
and magnitude of the HIV-specific CD8+ T cell responses increased progressively. Finally, whether HAART was initiated before or after
seroconversion had little effect on HIV-specific CD4+ and CD8+ T cell responses.
The Journal of Infectious Diseases 2003;187:748-757
Christine Lacabaratz-Porret,1 Alejandra Urrutia,1 Jean-Marc Doisne,1 Cecile Goujard,2 Christiane Deveau,3 Marc Dalod,4,a Laurence Meyer,3 Christine Rouzioux,5 Jean-Fran¨ois Delfraissy,2 Alain Venet,1 and Martine Sinet1
1Institut National de la Sante et de la Recherche Medicale (INSERM) E0109, 2Service de Medecine Interne, and 3INSERM U569, H™pital Bicetre, Le Kremlin Bicetre, 4INSERM U445 H™pital Cochin and 5Laboratoire de Virologie H™pital Necker, Paris, France
We studied 85 subjects from the multicenter French PRIMO cohort (Agence Nationale de Recherche sur le SIDA [ANRS] EP08). After providing informed consent, subjects were included, regardless of whether the PI was symptomatic. "HIV-1 PI" was defined as a recent high-risk HIV exposure with positive HIV RNA and a negative or evolving antibody response. After inclusion in the study, most subjects were treated with HAART. More recently, some individuals included in the cohort were untreated. Whole-blood samples were collected at regular intervals during the course of the study (months 0, 1, 3, and 6 and every 6 months thereafter).
The study population consisted of 85 subjects, 70 men and 15 women, with a median age of 35 years. All subjects were included at the time of PI with a median delay after the onset of symptoms of 24 days (interquartile range [IQR], 763 days). The subjects were divided into 2 groups according to each subject's Western blot profile. In the first group, the subjects had a negative or indeterminate Western blot at inclusion and were called "preseroconverters" or "acute" (n = 34); in the second group, the subjects entered the study in the period immediately
after seroconversion and were called "postseroconverters" or "early" (n = 51). In the acute group, all subjects had a symptomatic PI, and the median delay from the onset of symptoms to inclusion was 17 days; in the early group, 67%
of subjects were symptomatic, and the median delay from the onset of symptoms was 42 days.
DISCUSSION
Only few reports describe the effects of HAART on HIV-specific T cell responses during PI, of which some suggest that HAART preserves or enhances HIV-specific CD8+ T cell responses, whereas HIV-specific CD4+ T cell help is sustained. However, available immunological data are limited by small sample sizes, short duration of follow-up, and, often, lack of concomitant virological data. We provide detailed longitudinal data for HIV-specific immune responses from a large prospective cohort of subjects with PI with long-term follow-up in which different virological profiles related to various treatment interventions were examined. We found that CD4+ and CD8+ responses are modified by HAART but that these responses are differently influenced by changes in virus load. In addition, we show that the time when HAART is initiated has little effect on these responses when viremia is successfully controlled.
We found that CD4+ T cell proliferative responses are present but of low magnitude and are observed only in a minority of subjects (24%). These results are consistent with previous data that showed a comparable proportion of
subjects with positive responses to p24 antigen. As expected from previous studies, we observed a marked increase in proliferative responses in the group of treated subjects with sustained virological control. Moreover, we demonstrated that this response can be maintained up to 42 months after infection. A comparable increase of proliferative responses also was observed in the treated subjects with uncontrolled plasma HIV RNA levels, as well as
in the untreated subjects, which suggests that, at least in the first 18 months of infection, the existence of some degree of viral replication does not eliminate the proliferative response to HIV antigen. This is in clear contrast with previous studies that provided transversal data obtained from untreated subjects in the first months of infection, suggesting that they rarely developed p24-specific proliferative responses. However, our results are in accordance with an observation that 39% of untreated asymptomatic subjects had positive responses in another study. The subsequent increase in the proportion of subjects receiving HAART with an HIV-specific proliferative response in that study, as well as in others, also argues for the persistence of HIV-specific CD4+ T cells during later stages of infection. The discrepancy with previous results that described the lack of detectable specific T helper cell responses after immune reconstitution after HAART in chronically infected subjects may be related to the later initiation of therapy and the shorter follow-up period in the study reported by Autran et al.
The frequency of HIV-specific CD4+ T cells that produce IFN- was rather low at the time of PI, and these cells were rarely detectable by intracellular staining of IFN- and flow cytometry (data not shown). However, these specific
CD4+ T cells are detectable in 70% of the subjects, which is in contrast with the low percentage of subjects with proliferative responses. Discrepancies between proliferation and IFN- production during chronic infection already
have been described elsewhere. These studies pointed to the reduced proliferative ability of HIV-specific CD4+ T cells in subjects with high virus load, whereas IFN- production was maintained. Our data suggest that HIV-specific CD4+ T cells are already circulating during PI and maintaining their ability to produce IFN-, but with an impaired proliferative response due to both high virus load and CD4+ T cell depletion. During the follow-up period, the
frequency of IFN-producing cells was quite stable, and, in line with what was shown in chronic infection, we did not find evidence of any major influence of viral replication control on these changes. Altogether, these data suggest that HIV-specific CD4+ T cells are generated early in PI and that at least some of these cells may persist for a long period, even in the absence of complete virological suppression.
HIV-specific CD8+ T cells are thought to influence the viral set point. We have already shown that both the number of recognized epitopic peptides and the frequency of HIV-specific CD8+ T cells were low during PI. The present study confirms and extends these previous results. More particularly, our results confirm the very weak recognition of the 2 HLA-A*0201 restricted peptides, Gag 7785 and Pol 476484, that are described as immunodominant in chronic infection and the far better recognition of the epitopes restricted by HLA-B
molecules. Our data demonstrate that, as well as during chronic infection, the HIV-specific CD8+ T cell response decreases after initiation of therapy as long as virological suppression is maintained. A decrease in anti-HIV cytotoxic activity has been noticed in subjects treated during PI. By contrast, longitudinal data from subjects with continuously detectable plasma HIV RNA levels show a progressive and substantial increase in the breadth and
magnitude of HIV-specific CD8+ T cell response. Altogether, these results suggest that the persistence of viral antigens is the main determinant of the maintenance of specific CD8+ T cell responses at all stages of the disease.
The Th1 function of CD4+ T lymphocytes is presumed to be of key importance in host defense against HIV-1. Actually, several studies have shown that HIV-specific T helper cell responses play an important role in the effectiveness and maintenance of HIV-specific CD8+ T cell responses. A negative correlation of HIV-specific CD4+ helper T cell response with virus load has been described elsewhere [10]. This has been attributed to the relationship seen between virus-specific T helper and gag-specific CTL responses. Our baseline data do not show any relationship between either HIV-specific CD4+ or HIV-specific CD8+ T cell response and virus load. It is possible that maturation of both the CD4+ and the CD8+ specific T cell responses during PI is ongoing and that the equilibrium with virus load has not been reached. Moreover, we did not find any relationship between specific CD8+ T and CD4+ T cell responses. In some cases, we could detect HIV-specific CD8+ T cell responses in the absence of a detectable CD4+ T helper cell function. This is in accordance with recent results suggesting that HIV-specific CD8+ T cells could persist for long periods of time in the absence of virus-specific CD4+ T cells. In the latter case, the CD8+ effector cell function may be impaired, although this has been recently challenged.
Previous reports point to the potential advantage of initiating treatment very early, before seroconversion, to preserve or enhance HIV-specific T cell responses. It has been shown that some individuals who were treated
early were able to control HIV replication, at least transiently, after HAART was interrupted. This was thought to be related to the earliness of treatment, because such control is uncommon when HAART is stopped during chronic
infection. It has been suggested that this virological control could be related to a greater HIV-specific T cell immune response. In our study, the time when the therapy was initiated did not influence the evolution of HIV-specific CD4+ or
CD8+ T cell responses, as indicated by the similar changes of these responses in groups of acute and early subjects. Previous data suggested the existence of very high proliferation indices when treatment was initiated in acute infection,
before seroconversion. However, in our study, changes in HIV-specific CD4+ T cell responses were moderate and identical in both groups of subjects. Data from Altfeld et al. also suggested an increase of HIV-specific CD8+ T
cell responses with longer exposure to viral antigen. In fact, we did not find any increase in the breadth and magnitude of the HIV-specific CD8+ T cell responses in the group of early subjects, compared with that in the acute group. It should be mentioned that the subjects in the early group were treated after seroconversion but within 3 months of infection, as opposed to 6 months in the referenced study. This may explain why the HIV-specific CD8+ T cell response was still of low magnitude. Indeed, longitudinal data from subjects with continuously detectable plasma HIV RNA levels suggest that the time to obtain a significant increase in the breadth and magnitude of HIV-specific CD8+ T cell response is relatively long.
Altogether, the results provided here indicate that the hypothesis suggesting that only early treatment of HIV infection could preserve immune function can be moderated. Indeed, we found that subjects who started HAART at the
time of acute infection had no better HIV-specific T cell responses than those who started therapy after seroconversion. Furthermore, the absence of any treatment or the incomplete virological control did not prevent the development of an HIV-specific CD4+ T cell response, which suggests that the latter is preserved at least through the first 18 months of infection. However, these results are based on observational data. Therefore, early diagnosis probably was related to the severity of the disease, and subjects who remained untreated may have had less severe disease, in keeping with their lower plasma HIV RNA levels, than the treated subjects. Even so, our data point to the fact that an early therapy aimed at preserving the HIV-specific immune response may not be necessary in all subjects and that some individuals could remain untreated for some period of time, thereby avoiding the problems of drug toxicity and viral resistance by lack of treatment adherence. Immunological and virological markers that would identify these subjects are still to be
defined. Conversely, HAART induces a significant increase in CD4+ T cell numbers in subjects who efficiently control viral replication, which is thought to be beneficial. Additional controlled clinical trials could be warranted to clarify these points.
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