Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission.
A pilot study of a combination of highly active antiretroviral therapy (HAART) and cytokines in early HIV-1 infection has been undertaken to test the hypothesis that HIV-1 remission can be reached with this strategy by flushing latently infected viral reservoirs. Ten previously antiretroviral naive patients have received a combination of zidovudine, lamivudine, didanosine, saquinavir, and ritonavir for 72 weeks. Between weeks 12 and 48, three courses of interleukin (IL)-2 (7.5 millions of international units [MUI] twice a day for 5 consecutive days) and 2 courses of gamma-interferon (IFN) (100 microg every other day during 2 weeks) were administered subcutaneously. All patients reached plasma HIV-1 RNA levels < 20 copies/ml within 12 +/- 4 weeks. Transient increases in plasma levels (< 120 copies/ml) were observed during administration of IL-2, but less frequently during gamma-IFN administration. HIV-1 RNA decreased in lymph node cells by approximately 4 log, then remained stable after week 24. A mean drop of -0.8 log in peripheral blood mononuclear cell (PBMC) proviral DNA was observed during the trial. Isolation of potentially infectious HIV-1 was successful in each case by coculture of CD4+ T cells taken at week 72. The 2 patients who stopped therapy at the end of the trial showed rebounding plasma HIV-1 RNA levels within a few weeks. No additional mutations were selected in comparison with those present at baseline in 8 patients. In addition, 2 patients developed new mutations in the reverse transcriptase or protease gene and in 1 case, resistance selection was found in lymphoid tissue HIV-1 RNA but not in latently infected cells. In all cases, a rapid increase in both naive and memory CD4+ T cells was observed, with a reduction in activation markers and preservation of the CD8+CD28+ subset. Consequently, an aggressive regimen of HAART and cytokines administered in early stage disease is associated with a positive effect in terms of proviral load reduction and immune reconstitution but is unable to induce HIV-1 remission, allowing low levels of viral replication to persist in lymphoid reservoirs.
Lafeuillade
A
A
Department of Infectious Diseases, Laboratory of Virology, and Immunology Laboratory; General Hospital, Toulon, France. avps@club-internet.fr
Poggi
C
C
Chadapaud
S
S
Hittinger
G
G
Chouraqui
M
M
Pisapia
M
M
Delbeke
E
E
D000328:Adult; D017304:Annexin A5 / Q000032:analysis; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D002455:Cell Division; D018920:Coculture Techniques; D015331:Cohort Studies; D016207:Cytokines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008198:Lymph Nodes / Q000821:virology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011533:Proviruses / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000821:virology; D013997:Time Factors; D019562:Viral Load; D014766:Viremia / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000821:virology
D017304:Annexin A5; D019380:Anti-HIV Agents; D016207:Cytokines; D004279:DNA, Viral; D012367:RNA, Viral