 |
|
Incidence of HIV Superinfection Following Primary Infection
To the Editor: Anecdotal reports have suggested that individuals with preexisting human immunodeficiency virus (HIV) infection may be at risk for superinfection by different strains of HIV.1-3 We investigated the incidence of superinfection 6 to 12 months after a first diagnosis of HIV infection.
Methods
We included all recently infected antiretroviral-naive participants (n = 78) in the San Diego and Los Angeles Acute Infection and Early Disease Research Programs between December 1997 and June 2003 who had deferred antiretroviral treatment for at least the first 6 months after diagnosis. We retrospectively analyzed blood samples collected at the time of enrollment and then another sample 6 to 12 months later. Superinfection screening was performed on both sets of samples by population-based sequencing of pol from plasma HIV RNA using Viroseq version 2.0 (Celera Diagnostics, Foster City, Calif).
Superinfection was suspected when isolates from the same individual shared their most recent common ancestor during phylogenetic analysis with at least 1 other epidemiologically unrelated isolate.4 To distinguish these cases from coinfection, dye-primer sequencing of pol, length polymorphism analysis of env, and clonal sequencing of env were also performed and analyzed on samples from multiple time points, as previously described.3 Participants provided written informed consent. These studies were approved by the Human Research Protections Program at the Universities of California at San Diego and Los Angeles.
Results
Standard genotype sequencing of pol identified 3 potential cases of superinfection, representing a rate of 5.0% per year (95% confidence interval, 1.7%-13.3%). Further investigations, dye-primer sequencing of pol, length polymorphism analysis of env, and clonal sequencing of env (Figure 1) revealed no evidence of coinfection.2-3 We found no evidence of sample contamination or processing error by analyses of pol and env sequence and HLA antigen on additional samples (data not shown). Within 6 months of detecting the superinfecting strain, plasma viral loads increased (mean, 1.6 log10 copies/mL; range, 0.8-2.2) and CD4 cell counts decreased (mean decrease, 132 cells/µL; range, 150 to 347) in each of the 3 individuals. Furthermore, each was associated with a change in antiretroviral susceptibility. Two individuals, initially infected with drug-resistant HIV, were superinfected with a wild-type strain. The third was initially infected with a wild-type strain and was then superinfected with a drug-resistant strain.
|
|
|
|
Figure. Phylogram of 15-20 Clonal Sequences of the V3 Coding Region of env From Both Time-Point Samples From Each Individual Suspected of Being Superinfected
Circles indicate 3 individuals (A, B, and C) suspected of being superinfected, each with 2 isolates. Clonal sequences are clustered by time-point sample but not by individual. There was no intermingling of clonal sequences between time points, and sequence clusters differed by >8% homology and were separated by epidemiologically unrelated strains from 15 individuals in San Diego and Los Angeles (unlabeled branches) and laboratory strains (labeled branches).
|
|
|
Comment
We found that 4 independent laboratory approaches each suggested a 5% incidence of HIV-1 clade B superinfection within 6 to 12 months of initial infection. This rate is similar to the initial infection rate reported during a large HIV vaccine trial5 that enrolled HIV-negative individuals at risk for seroconversion, and thus may be similar to our cohort. It calls into question any protective effect of initial infection.
We also found that HIV superinfection had significant clinical implications. In 2 of the 3 individuals, the initially transmitted drug resistance would be masked by the wild-type superinfecting virus during routine drug-resistance testing. Antiretroviral therapy could be instituted that would unknowingly be ineffective. The third individual had undergone genotype testing that showed his virus to be susceptible to all antiretroviral medications but subsequently acquired a drug-resistant strain. Thus, he was prescribed an ineffective regimen that failed to suppress his superinfecting virus, as we previously described in an anecdotal report.3
In each of the 3 cases we report, the superinfecting virus had a greater in vivo fitness than the initial virus as evidenced by an increase in serum viral loads and a decrease in CD4 cell counts, similar to previous reports.1 This scenario of increased viral load and lower CD4 cell count portends a poorer prognosis independent of antiretroviral treatment options.6 Individuals already infected with HIV should thus continue vigilant personal protection through safe-sex practices or clean needle use for injection drugs, even if their risk exposures are with other HIV-infected people.
Access to Data: Dr Smith had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.
Funding/Support: This work was supported by National Institutes of Health grants 5K23AI055276, AI27670, AI38858, AI43638, AI43752, UCSD Centers for AIDS Research (AI36214), AI29164, and M01-RR00425, and the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Healthcare System.
Role of the Sponsors: The organizations funding this study had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
Davey M. Smith, MD
d13smith{at}ucsd.edu
Department of Medicine
University of California, San Diego
La Jolla
Joseph K. Wong, MD;
George K. Hightower, BA;
Caroline C. Ignacio, BS;
Kersten K. Koelsch, MD
Department of Medicine
University of California, San Diego
Eric S. Daar, MD
Division of HIV Medicine, Harbor-UCLA Research and Education Institute and the David Geffen School of Medicine at UCLA
Los Angeles, Calif
Douglas D. Richman, MD
Departments of Medicine and Pathology
University of California, San Diego
San Diego Veterans Affairs Healthcare Systems
Susan J. Little, MD
Department of Medicine
University of California, San Diego
1. Allen T, Altfeld M. HIV superinfection. J Allergy Clin Immunol. 2003;112:829-835.
FULL TEXT
| PUBMED
2. Koelsch KK, Smith DM, Little SJ, et al. Clade B HIV-1 superinfection with wild-type virus after infection with drug resistant clade B virus. AIDS. 2003,17:F11-F16.
FULL TEXT
|
ISI
| PUBMED
3. Smith DM, Wong JK, Hightower GK, et al. The clinical consequences of HIV superinfection. Presented at: XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand.
4. Gonzales MJ, Delwart E, Rhee SY, et al. Lack of detectable human immunodeficiency virus type 1 superinfection during 1072 person-years of observation. J Infect Dis. 2003;188:397-405.
FULL TEXT
| PUBMED
5. Watanabe ME. Skeptical scientists skewer VaxGen statistics. Nat Med. 2003;9:376.
PUBMED
6. Lyles RH, Munoz A, Yamashita TE, et al, Multicenter AIDS Cohort Study. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. J Infect Dis. 2000;181:872-880.
FULL TEXT
|
ISI
| PUBMED
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2004;292:1177-1178.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate
Yeh et al.
J. Virol. 2009;83:2686-2696.
ABSTRACT
| FULL TEXT
Human Immunodeficiency Virus Type 1 Superinfection Occurs despite Relatively Robust Neutralizing Antibody Responses
Blish et al.
J. Virol. 2008;82:12094-12103.
ABSTRACT
| FULL TEXT
Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection
Little et al.
J. Virol. 2008;82:5510-5518.
ABSTRACT
| FULL TEXT
Mapping Protease Inhibitor Resistance to Human Immunodeficiency Virus Type 1 Sequence Polymorphisms within Patients
Poon et al.
J. Virol. 2007;81:13598-13607.
ABSTRACT
| FULL TEXT
Prevalence and determinants of transmitted antiretroviral drug resistance in HIV-1 infection
Booth and Geretti
J Antimicrob Chemother 2007;59:1047-1056.
ABSTRACT
| FULL TEXT
Extensive Intrasubtype Recombination in South African Human Immunodeficiency Virus Type 1 Subtype C Infections
Rousseau et al.
J. Virol. 2007;81:4492-4500.
ABSTRACT
| FULL TEXT
Neutralizing Antibody Responses against Autologous and Heterologous Viruses in Acute versus Chronic Human Immunodeficiency Virus (HIV) Infection: Evidence for a Constraint on the Ability of HIV To Completely Evade Neutralizing Antibody Responses.
Deeks et al.
J. Virol. 2006;80:6155-6164.
ABSTRACT
| FULL TEXT
Evidence for Frequent Reinfection with Human Immunodeficiency Virus Type 1 of a Different Subtype
Chohan et al.
J. Virol. 2005;79:10701-10708.
ABSTRACT
| FULL TEXT
|
