Authors' reply to correspondence by Le and Farrar
Chun, Tae-Wooka; Moir, Susana; Kovacs, Colinb; Fauci, Anthony Sa
aLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
bDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada.
Received 30 December, 2010
Accepted 18 January, 2011
Correspondence to Tae-Wook Chun, PhD, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 6A32, 9000 Rockville Pike, Bethesda, MD 20892, USA. Tel: +1 301 496 0890; fax: +1 301 402 5920; e-mail: email@example.com
We appreciate the interest shown by Drs Thuy Le and Jeremy Farrar  regarding our paper entitled ‘Rebound of plasma viremia following cessation of antiviral therapy despite profoundly low levels of HIV reservoir: implications for eradication’ .
The authors inquired about the antiretroviral regimen of our study patient at the time of discontinuation of antiretroviral therapy (ART). Given a relatively long half-life of efavirenz , the patient's drug regimen was switched 2 weeks prior to discontinuation of ART, from abacavir, lamivudine, and efavirenz to abacavir, lamivudine, and lopinavir/ritonavir. We did so in order to prevent a possible emergence of efavirenz-resistance virus and to minimize the possibility that the initial lack of detectable plasma viremia following cessation of therapy may be due to the presence of low levels of efavirenz. We agree with the authors that it would be useful to carefully examine the reverse transcriptase gene of rebounding HIV. However, it is highly unlikely that non-nucleoside reverse transcriptase-resistant virus emerged nearly 64 days after efavirenz was withdrawn from the patient's drug regimen. The ethnicity of the patient we studied is Caucasian.
Drs Le and Farrar commented that additional information regarding the nature, kinetics, and fitness of immune-escaping HIV during the second viral rebound would have been interesting. However, as the authors pointed out, the main aim of this study was to examine the relationship between the size of persistent viral reservoirs and plasma viral rebound upon discontinuation of long-term ART. We can only speculate at this point that the host immune response, such as cytotoxic CD8+ T cells and neutralizing antibodies, may have played a role in suppressing plasma viremia following the first viral rebound after cessation of ART . It is clear that the host immune system ultimately failed to contain HIV replication after a brief period of aviremia. However, it will take a much larger cohort of long-term ART-treated infected individuals with extraordinarily low levels of viral reservoirs to better understand the interplay between re-emerging HIV following cessation of ART and the host immune responses. Such analyses could have important implications for research aimed at addressing the role of the immune response in controlling and ultimately eradicating virus in HIV-infected individuals.
Finally, Drs Le and Farrar pointed out that rebound of plasma viremia in our patient was inevitable as HIV may persist in multiple cellular and anatomical sites that may include hematopoietic progenitor cells [5,6]. In fact, we were able to detect replication-competent HIV in CD4+ T cells in the blood of our patient prior to discontinuation of ART. What was unique about this individual was that the sizes of his viral reservoir in blood and tissue were the lowest we had ever recorded in our laboratory. Drs Le and Farrar suggested that it would have been helpful to extend the duration of the off-ART period in order to study the kinetics of viral rebound and associated immunologic responses. Although our patient had a relatively high CD4+ T-cell count prior to discontinuation of ART and it is possible that his viremia could have been transiently controlled following the second viral rebound, previous studies involving interruption of ART have demonstrated that immunologic control of plasma viremia ultimately fails  and does not clinically benefit infected individuals . Furthermore, the decision to reinitiate ART was ultimately up to the patient and his primary care physician.
Identification of infected individuals with unique profiles, including initiation of ART during the early/acute phase of HIV infection, receiving therapy for extended periods of time, and carrying extraordinarily low levels of replication-competent virus, remains a major challenge to the field. We plan to continue examining such infected individuals and to conduct systematic analyses, such as those recommended by the authors in their correspondence, in order to better understand the pathogenesis of HIV disease and to possibly identify individuals who may have achieved a ‘functional cure’ .
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