Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy
Ngo-Giang-Huong, Nicolea; Deveau, Christianeb; Da Silva, Isabellea; Pellegrin, Isabellec; Venet, Alaind; Harzic, Martinee; Sinet, Martined; Delfraissy, Jean-Françoisf; Meyer, Laurenceb; Goujard, Cécilef; Rouzioux, Christinea; for the French PRIMO Cohort Study Group
From the aLaboratoire de Virologie, CHU Necker-Enfants Malades, Paris, France; bINSERM U292, Service d'Epidémiologie, Hôpital de Bicêtre AP-HP, Le Kremlin-Bicêtre, France; cLaboratoire de Virologie, Hôpital Pellegrin, Bordeaux, France; dLaboratoire Virus, Neurone et Immunité, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France; eLaboratoire de Microbiologie, Le Chesnay, France; and fService de Médecine Interne, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
Received: 10 August 2000;
revised: 5 January 2001; accepted: 10 January 2001.
Sponsorship: This work was supported by Agence Nationale de Recherches sur le SIDA (ANRS 97157). All subjects gave written informed consent for participation in the study. The project received authorization from the Ethical Committee.
Correspondence and reprint requests to: Nicole Ngo-Giang-Huong, Laboratoire de Virologie,
CHU Necker-Enfants Malades, 149 rue de Sèvres - 75015 Paris, France. Tel: +33 1 44 49 49 61; fax: +33 1 44 49 49 60; e-mail: email@example.com
Objective: An assessment of the impact of one year potent antiretroviral treatment initiated during primary HIV infection on the cell-associated viral burden.
Design and methods: Proviral HIV-1 DNA was quantified in serial peripheral blood mononuclear cell (PBMC) samples from 19 patients enrolled in the French prospective PRIMO Cohort for whom plasma HIV RNA was suppressed to undetectable levels after one year of triple therapy; that is, plasma HIV-1 RNA was maintained below 200 copies/ml. Results were compared with those observed in 19 patients with chronic HIV-1 infection presenting the same degree of virus suppression after 12 months of treatment.
Results: At study entry, PRIMO subjects presented heterogeneous levels of proviral HIV-1 DNA: 2–3.92 log10 copies/106 PBMC and plasma HIV RNA: 2.3–6.5 log10 copies/ml. One year of effective highly active antiretroviral therapy (HAART) resulted in a median diminution of proviral DNA of −0.78 log10/106 PBMC in PRIMO subjects. The median decline in chronic-phase patients was −0.32 for those who were pre-treated and −0.52 for those previously naive of treatment.
Conclusion: The decline in cell-associated HIV DNA observed throughout one year treatment indicated that HAART reduces the proviral HIV-DNA load more effectively when initiated during the primary rather than the chronic phase of HIV infection. These findings therefore tend to lend support to the early initiation of treatment. Nevertheless, heterogeneous baseline values observed for CD4 cell count, plasma HIV RNA and proviral HIV DNA in PRIMO subjects, raise the question of whether treatment should be delayed in some to spare early adverse effects of HAART.
The rationale for treating HIV infection radically and early stems from the hypothesis that the initiation of treatment soon after exposure to virus would enhance the suppression of virus replication and thus prevent the early loss of HIV-specific CD4 lymphocyte function [1–5]. Symptomatic primary infection, in particular when accompanied by neurological manifestations, has been shown to be associated with accelerated disease progression [6,7]. Studies in animals have suggested that the magnitude of early viraemia during acute infection may have a profound influence on the subsequent disease course , and outcome was improved when viral load was lowered at an early time-point by the adoptive transfer of neutralizing antibodies . Studies of the natural history of HIV-1 infection have indicated that the frequency of infected peripheral blood mononuclear cells (PBMC) is established within each individual immediately after seroconversion. Moreover, the viral burden in PBMC established early in infection correlated significantly with disease course , and the set-point of HIV RNA is critical for the prognosis of AIDS progression [11,12].
In 1996, the French prospective PRIMO Cohort Study was initiated with the primary objective of describing the natural course of primary HIV-1 infection (PHI), in order to gain further insight into the pathophysiology of HIV infection. A second objective was to study the natural history of HIV infection upon the early initiation of antiretroviral therapy in patients with PHI. Patients presenting with PHI were enrolled and followed up regularly. Blood samples were collected for immunological  and virological studies. Although no instruction regarding treatment was given, most of the patients were rapidly treated upon PHI diagnosis. We therefore investigated the impact of effective combination therapy on the peripheral blood reservoir. Quantification of proviral HIV-1 DNA was performed on serial blood samples taken throughout the first year from PRIMO individuals considered to be ‘effectively’ treated; that is, who attained undetectable levels of plasma HIV-1 RNA after one year of highly active antiretroviral therapy (HAART; threshold: 200 copies/ml). The results were compared with those of subjects with chronic HIV-1 infection, upon the initiation of triple therapy that included a protease inhibitor (PI). These chronic patients had either received no previous treatment (NRTI naive) or had received antiretroviral agents other than PI (PI naive). We describe baseline virological data at enrolment in the French Cohort Study (before treatment) and then present the evolution of proviral HIV DNA in ‘effectively’ treated patients.
Patients and methods
From November 1996 to March 1998, 79 patients presenting with presumed PHI were prospectively enrolled in the French PRIMO Agence Nationale de Recherches sur le SIDA (ANRS) Cohort Study. PHI was diagnosed when: (i) an initially negative test for HIV antibody was followed within 6 months by a positive serology; or (ii) a negative or indeterminate HIV enzyme-linked immunosorbent assay was associated with a positive p24 antigenaemia; or (iii) a Western blot profile was compatible with ongoing seroconversion (incomplete Western blot). The date of infection was estimated as the date of onset of symptoms minus 15 days or, when available, the date of incomplete Western blot minus 1 month, or by the midpoint between the negative and positive serological tests. All of the patients were naive of antiretroviral therapy at enrolment. Most of them began a 12 month antiretroviral treatment at this time. Patients were followed up regularly at 1, 3, 6 and 12 months. Clinical and biological data were collected at each visit.
For the baseline analysis, 30 PRIMO subjects were selected on the basis of the availability of blood samples and were studied in our laboratory. Among them, blood samples were available throughout a 1 year follow-up for 19 individuals who suppressed HIV replication to undetectable levels after 12 months of treatment; that is, their plasma HIV-1-RNA level was lower than 200 copies/ml. For comparison, we studied 19 subjects with chronic HIV-1 infection, previously described by Burgard et al.  and infected for at least 5 years. Combination antiretroviral treatment including one PI was initiated. Ten of these individuals were previously naive of treatment, whereas nine patients had already undergone antiretroviral therapy but without PI.
HIV-1 RNA in plasma
HIV RNA was measured in plasma samples on day 0 (enrolment in the cohort), and at 1, 6 and 12 months (M1, M6 and M12) with the Amplicor HIV Monitor assay (version 1.0; Roche Diagnostic Systems, Neuilly, France). Samples below 200 copies/ml were tested according to the ultra-sensitive specimen preparation protocol, which provides a detection limit of 20 copies/ml.
Quantification of proviral HIV-1 DNA
PBMC were isolated by standard Ficoll-hypaque density gradient centrifugation. Cells were frozen in aliquots of 3 × 106 PBMC, then stored at −80°C until use. HIV-DNA levels were quantified by using a prototypic assay developed at Roche Molecular Systems (Alameda, CA, USA) [4,15]. The level of proviral HIV DNA was measured by using a quantitative polymerase chain reaction method based on the Monitor test (Amplicor Monitor version 1.5) and by using an internal HIV DNA Standard (Roche). Total DNA was determined with Hoechst dye (Pharmacia, Uppsala, Sweden). Results are expressed as the number of HIV-DNA copies per million PBMC (threshold 5 copies/106 PBMC).
Data were analysed using SAS software. Non-parametric Spearman correlation coefficients were used to assess the association between continuous variables (plasma HIV RNA, proviral HIV DNA and CD4 lymphocyte count). Non-parametric analyses, Mann–Whitney test or Kruskal–Wallis analysis were used for comparing continuous variables between groups (PRIMO patients and chronic groups).
Baseline characteristics of PRIMO subjects
The virological characteristics and CD4 cell counts of the 30 PRIMO patients at study entry are presented in Table 1. The median time from the estimated date of infection to enrolment was 56 days (26–149 days). Patients were enrolled within a week from the diagnosis of primary infection. Twenty-one individuals were experiencing acute retroviral syndrome and nine were asymptomatic at enrolment. The CD4 lymphocyte count ranged from 156 to 1312 with a median value of 573 cells/μl. Plasma HIV-RNA levels ranged from 2.3 to 6.5 log10 HIV-1 RNA copies/ml, with a median value of 4.6. As expected, the level of plasma HIV RNA was higher in subjects with positive p24 antigen than with negative p24 antigen (P < 0.0001) (Fig. 1a).
Proviral HIV DNA was determined in PBMC and showed a less extended distribution, from 2 to 3.92 log10 HIV-1 DNA copies/106 PBMC, with a median value of 2.91. Proviral HIV-1 DNA at study entry was positively correlated with plasma HIV RNA (P < 0.001) and higher HIV-DNA values were associated with positive p24 antigen (P = 0.003) (Fig. 1a). In addition, proviral HIV DNA was negatively correlated with the CD4 lymphocyte count (P = 0.046) (Fig. 1b).
The clinical characteristics of patients with chronic HIV-1 infection, before the initiation of HAART, are given Table 2. The CD4 lymphocyte count ranged from 1 to 888, with a median value of 103 cells/μl. Plasma HIV-RNA levels ranged from 3.8 to 6.5 log10 HIV-1-RNA copies/ml, with a median value of 4.92. Proviral HIV DNA extended from 2 to 3.92 log10 HIV-1-DNA copies/106 PBMC, with a median value of 3.26.
Evolution of proviral HIV-1 DNA in 19 PRIMO subjects with plasma HIV-RNA level less than 200 copies/ml after 12 months of treatment
The evolution of plasma HIV RNA under HAART in PRIMO subjects and the two groups of patients with chronic HIV-1 infection, naive or pre-treated, are presented in Fig. 1a. A very similar pattern of decline in plasma HIV RNA in response to treatment was observed in the three groups. Within the PRIMO group, plasma HIV-1 RNA diminished to less than 20 copies/ml for two subjects after 1 month, six subjects after 3 months, 14 subjects after 6 months, and 16 subjects after 12 months of treatment.
By comparison, the pattern of decline in proviral HIV DNA under treatment, presented in Fig. 2b, is quite different. The median level of proviral HIV DNA was 2.81 before the initiation of active antiretroviral treatment. After 1 month of treatment, the median level was 2.75 log10 DNA copies/106 PBMC, after 6 months, 2.34, and after 12 months the median level of proviral DNA attained 2.14 log10 DNA copies/106 PBMC.
When compared with the patients with chronic HIV infection who were previously naive of treatment, the median proviral HIV-DNA level, before the initiation of HAART, was significantly lower in the PRIMO group (2.81 log10 DNA copies/106 PBMC) than in the chronic group (3.59 log10 DNA copies/106 PBMC) (P = 0.02). Despite this lower level, HAART was more active on proviral HIV DNA when initiated during PHI than in the chronic phase, as evidenced by the decrease in cellular HIV-1 DNA observed after 6 months of HAART: −0.51 versus −0.30, respectively (P = 0.05) (Fig. 3). Between 6 and 12 months of treatment, a similar decrease was observed in the two groups (P = 0.42). The net result after 12 months of follow-up was of borderline significance, −0.78 log versus −0.52 (P = 0.12) (Fig. 3), perhaps because of the small sample size.
Interestingly, those patients with chronic HIV infection who were pre-treated before the initiation of PI and PRIMO subjects had similar initial levels of proviral HIV DNA (P = 0.35), but differed in their response to treatment. Indeed, the diminution in proviral HIV DNA was more pronounced in PRIMO patients (−0.78) than in chronic-phase patients (−0.32) at 12 months (P = 0.005) (Fig. 3). The pattern of decline in proviral HIV DNA observed in the three groups was thus different from that observed for plasma HIV-1 RNA (Fig. 3).
We have thus analysed whether this more pronounced decrease in PRIMO patients was dependent on the baseline proviral DNA level. The initial proviral DNA load was found to be correlated with the proviral load at 12 months (Spearman test r = 0.76, P = 0.0013), but not with the decrease in plasma viraemia achieved after 12 months (P = 0.72). Despite a homogeneous decline in plasma HIV RNA, a heterogeneous decrease in proviral HIV DNA was observed. Marked decreases in proviral HIV-1 DNA between baseline and M12 could thus be observed both in subjects with high or low levels of proviral HIV-1 DNA (Fig. 4).
Some years ago, the efficacy of combination therapy that includes a PI in suppressing HIV replication led to the belief that the early treatment of HIV-infected individuals, and in particular when initiated during PHI, might well eradicate the virus. Currently available antiretroviral therapies, however, fail to achieve this objective, even when administered soon after the first symptoms of PHI [3,4,16–19]. Nonetheless, it has been suggested that treatment at this early stage, although not eradicating the virus, might at least efficiently control viraemia and thus prevent the loss of HIV-specific CD4 T cell responses [2,5]. These HIV-specific CD4 T cell responses have been strongly and inversely correlated with the viral burden in vivo, although prolonged viral suppression caused by antiretroviral therapy has resulted in a decline in functional HIV-specific CD4 T cells . Nevertheless, early treatment during PHI does appear to provide an immunological benefit, as evidenced by the persistence of HIV-specific CD4 responses in PRIMO subjects on active antiretroviral therapy (Venet et al., personal communication).
In patients under HAART, plasma viraemia is rapidly suppressed to undetectable levels [3,4,14,19,21–29], even though low-level replication is ongoing. For this reason, proviral HIV DNA could be a more informative marker than plasma HIV RNA with which to assess the long-term impact of treatment . It is not known to what extent this low-level replication is responsible for replenishing the pool of HIV-infected cells, but our results indicate that HAART can reduce the proviral HIV-DNA load more efficiently when initiated during PHI than during the chronic phase. Our results also underscore the importance of effective initial treatment, even when initiated in the chronic phase. Indeed, although the median decrease in proviral HIV DNA observed in patients who were previously naive of treatment was −0.72 and −0.52 for individuals with primary and chronic HIV-1 infection, respectively, this decrease was less pronounced (−0.32 log) in pre-treated chronic-phase patients. Zaunders et al. , however, reported that untreated PHI patients and patients treated within 45–90 days from the onset of symptoms had comparable HIV-DNA levels, and therefore suggested that HAART had little effect on the HIV-DNA burden established after acute infection. We cannot rule out the hypothesis that the more pronounced effect of early HAART treatment relative to delayed HAART on the proviral decline could be ascribed to the evolving immune response during the acute phase of infection. Early HAART treatment would be beneficial by preventing ongoing dissemination and thus by maintaining a low viral DNA reservoir.
The reservoir of latently infected cells is established early during PHI [4,16,31]. Over the ensuing course of infection, Lee et al.  described this reservoir as remaining stable after seroconversion, whereas Cone et al.  observed a moderate increase in HIV-DNA levels in PBMC. In our study, cross-sectional results of initial proviral HIV DNA in patients in primary versus chronic infections suggest that the pool of latently infected CD4 cells increased over time, although subjects with chronic HIV infection who were previously naive of treatment represented a small group. We do not know the precise date of infection for the group of chronic stage patients, but the time elapsed between initial infection and the initiation of HAART was more than 5 years. Our technique could not differentiate replication-competent from defective HIV-1 proviral DNA, but it is likely that both have probably accumulated in these patients during the period without HAART. This is compatible with our results of substantially higher HIV-1-DNA levels in this group (3.59 log10 DNA copies/106 PBMC) compared with the PRIMO group (2.81 log10 DNA copies/106 PBMC) (P = 0.02).
Taken together, our results argue in favour of the therapeutic advantage of early treatment of HIV infection, and lend support to the early initiation of therapy. Nevertheless, this view should be tempered by the fact that lifelong treatment may be required. Indeed, treated patients face problems of tolerance owing to the numerous side-effects and toxicity of retroviral inhibitors, as well as problems of therapeutic failure, underscoring the limitations of long-term therapy, which would be even further strained were treatment initiated in primary infection.
Moreover, before the initiation of treatment certain PRIMO patients not only had a high CD4 cell count, but also low levels of plasma HIV RNA and proviral HIV DNA. We may hypothesize that some of those individuals are capable of spontaneously controlling virus replication for years without any treatment. We could thus spare side-effects or toxicity such as lipodystrophy, which may even occur in PHI-treated patients. Why some PRIMO patients had low viral burdens while others had high burdens is not yet understood. The level of proviral DNA is probably peculiar to the individual, because host genetic factors, such as chemokine receptor gene polymorphisms, which are determinants for disease progression  and the response to treatment [34,35], are likely to be involved in the establishment of the pool of HIV-infected cells.
Our study shows that heterogeneous viral loads are observed early after PHI and that, upon the initiation of HAART, responses are heterogeneous. Further studies are needed to assess the predictive value of the HIV-DNA level for the infection outcome. The quantitative analysis of proviral DNA, before the initiation of antiretroviral therapy, could be a constructive marker for arguing for treatment of PHI. At present, because of the growing evidence on the side-effects and toxicity of HAART and the need for lifelong treatment, some physicians question the moment of treatment initiation for PHI patients, in that some of them might spontaneously control viral replication for years. A large-scale randomized study of early therapy with careful proviral load assessment is thus needed to delineate further the moment to commence antiretroviral therapy in the primary infection period.
The authors are indebted to the patients enrolled in the French PRIMO Cohort Study and to our clinician colleagues, without whom none of these studies would have been possible. The authors gratefully acknowledge the French HIV Quantification Group for data concerning HIV-1-infected patients in chronic phase. They would also like to thank Dr J. Richardson for reviewing the manuscript.
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Primo Cohort Study Group: C. Caulin, J. Cervoni, E. Badsi (Lariboisière, Paris); F. Raffi, V. Reliquet, E. Billaud, J.L. Esnault (Hôtel-Dieu, Nantes); A.P. Blanc, T. Allegre (Aix en Provence); M. Dorra, J. Derouineau, S. Morelon, E. Rouveix (A. Paré, Boulogne); G. Sobesky, S. Abel, A. Cabié (Fort de France); P. Henon, G. Beck-Wirth (Emile Muller, Mulhouse); C. Bazin, M. Six, R. Verdon (Caen); S. Herson, N. Amirat, J. Dagron (Pitié-Salpétrière, Paris); J. Beylot, P. Morlat, D. Malvy, M. Bonarek (Saint André, Bordeaux); P. Morel, F. Timsit (St Louis, Paris); J.P. Cassuto, C. Sohn (L'Archet, Nice); J.L. Vildé, C. Jestin, C. Jadand, U. Colasante (Bichat, Paris); J.F. Delfraissy, C. Goujard, X. Copin, Y. Quertainmont (Bicêtre, Le Kremlin Bicêtre); D. Sicard, D. Salmon, G. Spiridon (Cochin, Paris); G. Charpentier, P. Chevojon (Corbeil); J. Achard, P. Fialaire (Angers); F. Vachon, E. Bouvet, I. Fournier (Bichat, Paris); J.F. Bach, J.P. Viard (Necker, Paris); B. Dupont, C. Joly (Pasteur, Paris); R. Laurent, C. Drobacheff, Y. Bourezane (St Jacques, Besançon); H. Gallais, A.M. Quinson, I. Ravaux (La Conception, Marseille); P. Dellamonica, S. Chailloux (L'Archet, Nice); M. Kazatchkine, D. Laureillard (Broussais, Paris); J. Beytout, C. Jacomet (Hôtel Dieu, Clermont-Ferrand); J. Laffay, A. Greder Belan (A. Mignot, Le Chesnay); J.C. Imbert, O. Picard (St Antoine, Paris); O. Bletry, D. Zucman (Foch, Suresnes); P. Galanaud, F. Boué (A. Béclère, Clamart); J.C. Messmer, B. Delmas (Joffre, Perpignan); Ph. Vinceneux, A.M. Simonpoli (L. Mourier, Colombes); A. Sobel, P. Lesprit (H. Mondor, Créteil); M. Gayraud, L. Bodard (I.M.M. Jourdan, Paris); D. Sereni, C. Lascoux (St Louis, Paris); M. Chousterman, O. Launay (Créteil); T. Colin, V. Launay (Cherbourg); P. Chavanet, M. Buisson (Dijon); F. Jambon, V. Baillat (Montpellier); D. Merrien (Compiegne); G. Dien, C. Hascoet (Saint Brieuc); D. Houlbert (Alençon); J.P. Clauvel, L. Gérard (St Louis, Paris); J.P. Coulaud, M. Saada (Bichat, Paris); G. Guermonprez, A. Dulioust (Briis s/Forges); Gonzalez, F. Sanlaville (Sens); C. Miodovski (Paris); P. Boudon, D. Malbec (R. Ballanger, Aulnay Sous Bois); J. Deville, I. Beguinot (Robert Debré, Reims).
Highly active antiretroviral therapy; primary HIV-1 infection; proviral HIV-1 DNA
© 2001 Lippincott Williams & Wilkins, Inc.
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