editorials

ficient clinical events. A consensus on a single

vessel area for investigation might provide a
single cutoff value for the resistive index. This
should allow an assessment of whether the resistive index predicts recipient death, renal survival, or both, the results of which would define
the role of the resistive index in the assessment
of transplant patients.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Department of Nephrology, Johannes Wesling Klini
kum Minden, Minden (J.R.), and the Department of Nephrology,
Hannover Medical School, Hannover (H.H.) both in Germany.
1. Barba J, Rioja J, Robles JE, et al. Immediate renal Doppler

ultrasonography findings (<24h) and its association with graft

survival. World J Urol 2011;29:547-53.
2. Elster EA, Hale DA, Mannon RB, et al. Surgical transplant
physical examination: correlation of renal resistance index and
biopsy-proven chronic allograft nephropathy. J Am Coll Surg
2005;200:552-6.
3. Kolonko A, Chudek J, Zejda JE, Wiecek A. Impact of early
kidney resistance index on kidney graft and patient survival during a 5-year follow-up. Nephrol Dial Transplant 2012;27:1225-31.

4. Loock MT, Bamoulid J, Courivaud C, et al. Significant in-

crease in 1-year posttransplant renal arterial index predicts graft

loss. Clin J Am Soc Nephrol 2010;5:1867-72.
5. Radermacher J, Mengel M, Ellis S, et al. The renal arterial
resistance index and renal allograft survival. N Engl J Med 2003;
349:115-24.
6. Bude RO, Rubin JM. Relationship between the resistive index
and vascular compliance and resistance. Radiology 1999;211:
411-7.
7. Tublin ME, Tessler FN, Murphy ME. Correlation between
renal vascular resistance, pulse pressure, and the resistive index
in isolated perfused rabbit kidneys. Radiology 1999;213:258-64.
8. Schmieder RE, Schchinger H, Messerli FH. Accelerated decline in renal perfusion with aging in essential hypertension.
Hypertension 1994;23:351-7.
9. Castleman B, Smithwick RH. The relation of vascular disease to the hypertensive state; the adequacy of the renal biopsy
as determined from a study of 500 patients. N Engl J Med 1948;
239:729-32.
10. Ishii Y, Sawada T, Kubota K, Fuchinoue S, Teraoka S, Shimizu A. Injury and progressive loss of peritubular capillaries in
the development of chronic allograft nephropathy. Kidney Int
2005;67:321-32.
11. Naesens M, Heylen L, Lerut E, et al. Intrarenal resistive index
after renal transplantation. N Engl J Med 2013;369:1797-806.
DOI: 10.1056/NEJMe1312281
Copyright 2013 Massachusetts Medical Society.

Baby Steps on the Road to HIV Eradication

Scott M. Hammer, M.D.
The durable suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA that is
conferred by potent antiretroviral therapy (ART)
has been associated with dramatic improvements
in immunologic and clinical well-being and reductions in morbidity and mortality from opportunistic complications. It has also brought the
restoration of normal life expectancies within our
grasp, has effectively eliminated the vertical transmission of HIV in resource-unconstrained settings
in women who receive antenatal care, and can
substantially reduce horizontal transmission.1
Concomitantly, the ability to drive plasma
HIV-1 RNA to levels below the limits of quantification of sensitive clinical assays has unveiled
the limitations of our current knowledge and
therapies. Residual viremia, defined as less than
20 copies of plasma HIV-1 RNA per milliliter,
can be detected in most persons receiving effective therapy, and replication-competent virus can
be isolated from peripheral-blood CD4+ T cells
cultured ex vivo from such patients. The bestdescribed cellular reservoir is the resting, memory CD4+ T cell, but other cell types probably
contribute.2 The persistence of the virus in cell

reservoirs is thought to feed the residual viremia

by means of intermittent release of infectious
virus rather than by rounds of ongoing viral
replication, although this point is still debated.2
The persistence of HIV in reservoirs has at least
two major implications: it may be responsible for
the ongoing immune activation and inflammatory state seen in virologically suppressed persons, which, in turn, may be linked to the nonopportunistic complications of cardiovascular,
renal, hepatic, and malignant disease; and, with
integrated HIV proviral DNA, this reservoir pre
sents the biggest challenge to achieving the complete eradication of replication-competent HIV-1
from an infected person.
There has been one well-documented case of
an adult in whom the eradication of replicationcompetent HIV-1 (i.e., a cure) has been achieved.3
This person required a hematopoietic stem-cell
transplant for acute myelogenous leukemia, with
the donor being homozygous for the 32-base-pair
deletion in the chemokine (C-C motif) receptor
5 gene (CCR5 delta32), making the patients engrafted lymphocytes resistant to infection with
the R5 (CCR5-tropic) HIV-1 strain. Bone marrow

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n e w e ng l a n d j o u r na l

ablation and graft-versus-host disease also probably contributed to the cure in this patient, which
has now been documented for more than 5 years.4
Other reports of reductions of the viral reservoir
after hematopoietic stem-cell transplantation
for the treatment of lymphoma or early ART have
subsequently appeared that support the hypothesis that the HIV reservoir is a viable therapeutic
target.5-7
Persaud and colleagues8 now describe in the
Journal a case of a child who was born at 35 weeks
of gestation to an HIV-infected mother who had
not received prenatal care and thus was not receiving ART at the time of delivery. The child
began receiving combination ART 30 hours after
birth, and the subsequent early course was notable for the decreasing but detectable viremia
through 19 days of age. After a 5-month absence
from care, during which ART was not administered, viral rebound was not detected when the
child presented again at 23 months of age.
Challenging questions have been raised by
this case. Was infection established in the infant?
Are the early virologic findings a result of maternalfetal circulatory exchange? Could this be a
case of postexposure prophylaxis? The positive
HIV-1 DNA polymerase chain reaction drawn at
30 hours and the plasma HIV-1 RNA level of
19,812 copies per milliliter drawn separately at
31 hours taken together meet the criteria for neonatal infection, and the early test positivity is
compatible with in utero, rather than intrapartum, infection. The transfer of maternal cells and
virions would probably not result in an HIV-1
RNA level that was eight times as high in the
neonate as it was in the mother (maternal viral
load at 24 hours, 2423 copies per milliliter), nor
would it result in 19 days of viremia. These data,
along with the classic trajectory of viremic decline during ART, support the authors perspective that the infant was truly infected.
The big question, of course, is, Is the child
cured of HIV infection? The best answer at this
moment is a definitive maybe. This uncertainty
is due to the need for long-term follow-up while
the child is not receiving ART and the imprecision with which the viral reservoir can be measured. Assays for proviral DNA in the child at 24
and 26 months of age were inconclusive, but the
failure to isolate replication-competent HIV-1
from resting CD4+ T cells and the absence of

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m e dic i n e

rebound viremia months after ART was discontinued are compelling.

The eradication of HIV-1 is now the goal of a
formidable research effort. One line of investigation is focused on reducing, destabilizing, or
eliminating the latent cell reservoir. Drugs such
as the histone deacetylase inhibitors (e.g., vorinostat) can disrupt the epigenetic control of integrated provirus, resulting in viral RNA transcription.9 However, this may not result in reliable
killing of the cell, which suggests that the addition of an immune effector mechanism may be
necessary to ensure the death of these cells.10
Destabilization of the viral reservoir can also be
achieved by engaging the programmed death 1 receptor on the surface of latently infected CD4+
T cells. Another line of investigation being pursued is gene therapy directed at interrupting the
expression of CCR5 coreceptors.11
The child described by Persaud et al. may be
unique, and thus we have to exercise caution before inferring general principles from this case
report. This said, we are at the stage at which
individual case reports can provide proofs of principle, stimulate hypotheses, and lead to carefully
designed experimental therapeutic studies involving both adults and children that, we hope, will
lead us down the road to the reduction or eradication of the HIV-1 reservoir. To paraphrase the
Chinese philosopher, Lao-tzu, A journey of a
thousand miles begins with a single step. In the
case of HIV infection, this may turn out to be a
baby step.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Division of Infectious Diseases, Department of Medi
cine, Columbia University Medical Center, New York.
This article was published on October 23, 2013, at NEJM.org.
1. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treat-

ment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012;308:387-402.
2. Siliciano JD, Siliciano RF. HIV-1 eradication strategies: design and assessment. Curr Opin HIV AIDS 2013;8:318-25.
3. Htter G, Nowak D, Mossner M, et al. Long-term control of
HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J
Med 2009;360:692-8.
4. Yukl SA, Boritz E, Busch M, et al. Challenges in detecting
HIV persistence during potentially curative interventions: a study
of the Berlin patient. PLoS Pathog 2013;9(5):e1003347.
5. Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity
conditioning allogeneic stem cell transplantation. J Infect Dis
2013;207:1694-702.

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editorials
6. Ananworanich J, Schuetz A, Vandergeeten C, et al. Impact of

multi-targeted antiretroviral treatment on gut T cell depletion

and HIV reservoir seeding during acute HIV infection. PLoS One
2012;7(3):e33948.
7. Sez-Cirin A, Bacchus C, Hocqueloux L, et al. Posttreatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 2013;9(3):e1003211.
8. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable
HIV-1 viremia after treatment cessation in an infant. N Engl J
Med 2013;369:1828-35.

9. Archin NM, Liberty AL, Kashuba AD, et al. Administration

of vorinostat disrupts HIV-1 latency in patients on antiretroviral

therapy. Nature 2012;487:482-5. [Erratum, Nature 2012;489:460.]
10. Shan L, Deng K, Shroff NS, et al. Stimulation of HIV-1specific cytolytic T lymphocytes facilitates elimination of latent
viral reservoir after virus reactivation. Immunity 2012;36:491501.
11. Kent SJ, Reece JC, Petravic J, et al. The search for an HIV
cure: tackling latent infection. Lancet Infect Dis 2013;13:614-21.
DOI: 10.1056/NEJMe1309006
Copyright 2013 Massachusetts Medical Society.

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