In the 11/1/05 Journal of Clinical Investigation article titled
"HIV-infected individuals receiving effective antiviral therapy for
extended periods of time continually replenish their viral reservoir,"
Chun et al. (Fauci is senior author) state:

"In the present study, we investigate the presence and status of
residual HIV in patients who had received effective antiviral therapy
for up to 9.1 years and examine the underlying mechanisms by which HIV
persists in CD4+ T cells of such individuals. We demonstrate that all
infected subjects studied carried replication-competent HIV in their
CD4+ T cells and the majority of patients harbored considerable levels
of HIV proviral DNA in their activated as well as resting CD4+ T cell
compartments. Finally, we also provide evidence for cross infection
between these 2 compartments, suggesting a possible mechanism by which
HIV persists in patients who are receiving clinically effective
antiretroviral therapy."

"In the present study, we investigated the source(s) and the extent of
residual HIV replication and examined the underlying mechanisms by which
HIV persists in CD4+ T cells of patients who received effective
antiviral therapy for extended periods of time. We demonstrated
that all infected subjects examined carried replication-competent HIV in
their CD4+ T cells despite having received clinically effective
antiviral therapy for extended periods of time (8.3 years on average).
To our knowledge, this is the first study to examine levels of
replication-competent HIV in the CD4+ T cell compartments of patients
who have received effective antiviral therapy for such long periods of
time (up to 9.1 years). We also demonstrated that, contrary to current
dogma, it is the activated CD4+ T cell compartment that harbors the
majority of persisting HIV in infected individuals who have had no
detectable viremia for extended periods of time as a result of effective
antiretroviral therapy. In the years following the first indications of
HIV latency in infected individuals, the vast majority of studies, if
not all, addressing the persistence of HIV in the era of effective
antiviral therapy focused heavily on the latent viral reservoir in the
resting CD4+ T cell compartment as a major impediment to eradication of
HIV. However, the activated CD4+ T cell compartment has not been fully
explored as a potential viral reservoir in infected individuals
receiving clinically successful antiviral therapy mainly because it has
been believed that such cells are short lived and not expected to harbor
virus. By demonstrating the presence of HIV in activated CD4+ T cells of
maximally suppressed individuals, we thus provide compelling evidence
for contribution of this compartment to the continual reseeding of HIV
reservoirs. Although mitotic division of activated CD4+ T cells
harboring defective virus could account for the higher frequency of
cells carrying HIV proviral DNA in activated CD4+ T cell compartments
compared with resting CD4+ T cell compartments, the evidence presented
herein for spontaneous release of virions and viral migration and the
short half-life of activated CD4+ T cells would argue for the
persistence of infectious virus in activated CD4+ T cells."

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This Article FREE, OPEN ACCESS

J. Clin. Invest. 2005 Nov 1;115:3250-3255. doi:10.1172/JCI26197.

HIV-infected individuals receiving effective antiviral therapy for
extended periods of time continually replenish their viral reservoir

Tae-Wook Chun1, David C. Nickle2, J. Shawn Justement1, Danielle Large1,
Alice Semerjian1, Marcel E. Curlin2, M. Angeline O'Shea1, Claire W.
Hallahan3, Marybeth Daucher1, Douglas J. Ward4, Susan Moir1, James I.
Mullins2, Colin Kovacs5 and Anthony S. Fauci1

1Laboratory of Immunoregulation, National Institute of Allergy and
Infectious Diseases, NIH, Bethesda, Maryland, USA.
2Department of Microbiology, University of Washington, Seattle,
Washington, USA.
3Biostatistical Research Branch, National Institute of Allergy and
Infectious Diseases, NIH, Bethesda, Maryland, USA.
4Dupont Circle Physicians Group, Washington, DC, USA.
5Department of Medicine, University of Toronto, Toronto, Ontario,
Canada.

Address correspondence to: Tae-Wook Chun, Laboratory of
Immunoregulation, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Building 10, Room 6A32, 9000 Rockville
Pike, Bethesda, Maryland 20892, USA. Phone: (301) 496-0890; Fax: (301)
402-5920; E-mail: twchun{at}nih.gov.

Received for publication July 7, 2005, and accepted in revised form
August 23, 2005.

Abstract: The persistence of latently infected, resting CD4+ T cells is
considered to be a major obstacle in preventing the eradication of HIV-1
even in patients who have received effective antiviral therapy for an
average duration of 5 years. Although previous studies have suggested
that the latent HIV reservoir in the resting CD4+ T cell compartment is
virologically quiescent in the absence of activating stimuli, evidence
has been mounting to suggest that low levels of ongoing viral
replication persist and in turn, prolong the overall half-life of HIV in
patients receiving antiviral therapy. Here, we demonstrate the
persistence of replication-competent virus in CD4+ T cells in a cohort
of patients who had received uninterrupted antiviral therapy for up to
9.1 years that rendered them consistently aviremic throughout that time.
Surprisingly, substantially higher levels of HIV proviral DNA were found
in activated CD4+ T cells when compared with resting CD4+ T cells in the
majority of patients we studied. Phylogenetic analyses revealed evidence
for cross infection between the resting and activated CD4+ T cell
compartments, suggesting that ongoing reactivation of latently infected,
resting CD4+ T cells and spread of virus by activated CD4+ T cells may
occur in these patients. Such events may allow continual replenishment
of the CD4+ T cell reservoir and resetting of the half-life of the
latently infected, resting CD4+ T cells despite prolonged periods of
aviremia.