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Original Article

Inhibition of HIV-1 Disease Progression by Contemporaneous HIV-2 Infection

List of authors.
  • Joakim Esbjörnsson, Ph.D.,
  • Fredrik Månsson, M.D., Ph.D.,
  • Anders Kvist, Ph.D.,
  • Per-Erik Isberg, M.Sc.,
  • Salma Nowroozalizadeh, Ph.D.,
  • Antonio J. Biague, M.D.,
  • Zacarias J. da Silva, M.D., Ph.D.,
  • Marianne Jansson, Ph.D.,
  • Eva Maria Fenyö, M.D., Ph.D.,
  • Hans Norrgren, M.D., Ph.D.,
  • and Patrik Medstrand, Ph.D.

Abstract

Background

Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood.

Methods

We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution.

Results

The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection.

Conclusions

Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency–Swedish Agency for Research Cooperation with Developing Countries and others.)

Introduction

More than 60 million people have been infected with the human immunodeficiency virus (HIV), and despite tremendous efforts, there is no cure or effective vaccine against the virus. The natural course of HIV infection is usually described in three stages. The acute infection stage is characterized by viremia, a rapid decrease in CD4+ T-cell count, and development of influenza-like symptoms. In the asymptomatic stage, a continuous and moderate decline in T-cell counts is seen. Finally, in the acquired immunodeficiency syndrome (AIDS) stage, opportunistic diseases develop, owing to a dysfunctional immune system. The duration of the three stages, especially the asymptomatic stage, can differ considerably among infected persons.

Two important human lentiviruses have been described: pandemic HIV type 1 (HIV-1), and HIV type 2 (HIV-2), which is mainly confined to West Africa. Both viruses have similar transmission routes, cellular targets, and AIDS-defining HIV-related symptoms. However, as compared with HIV-1 infection, HIV-2 infection is characterized by lower transmission rates, a longer asymptomatic stage, a slower decline in CD4+ T-cell counts, and a lower mortality rate.1-4 Progressive immune dysfunction and AIDS develop in most persons who have untreated infection with HIV-1 only, as compared with only 20 to 30% of persons infected with HIV-2 only.

In West Africa, the prevalence of dual infection with HIV-1 and HIV-2 has been reported as 0 to 3.2%.5,6 In 1995, a possible protective effect of HIV-2 against subsequent HIV-1 infection in commercial sex workers in Senegal was reported.7 This protective effect could not be verified in other cohorts.8,9 However, several studies have reported that HIV-2 infection can alter HIV-1 infectivity and replication in vitro, suggesting that HIV-2 infection may inhibit the rate of HIV-1 disease progression.10-12 Studies of natural disease progression among persons with both HIV-1 and HIV-2 infection have, however, been limited by low numbers of study participants, short follow-up times, and lack of data on the time of infection.13

Methods

Study Conduct

The study was approved by the ethics committees of the government of Guinea-Bissau, the University of Lund, Sweden, and the Karolinska Institute, Stockholm. Study participants were counseled and provided informed oral consent.

Study Population

We enrolled participants in our prospective study from February 6, 1990, through December 31, 2007. All persons with regular employment in the Guinea-Bissau police force were eligible, and over 98% enrolled. Blood samples were collected for serologic testing for HIV and measurement of T-cell counts, which were conducted at the National Public Health Laboratory of Bissau as previously described,6,14 at enrollment and at follow-up visits every 12 to 18 months until September 1, 2009. Antiretroviral therapy was introduced in Guinea-Bissau in 2005 through a national treatment program. The police cohort was included in the program in early 2006. The few study participants receiving antiretroviral therapy had data censored at the time of initiation of antiretroviral therapy. The date of HIV-1 seroconversion was estimated as the middle of the interval between the last HIV-1–seronegative sample and the first HIV-1–seropositive sample. (For more details on the study population, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Epidemiologic Analysis

Kaplan–Meier analysis was performed for time to the development of AIDS (time to AIDS) according to CD4+ T-cell counts, clinical criteria, and reported death with symptoms of AIDS (Centers for Disease Control and Prevention stage C and World Health Organization stage 4).15,16 The proportions of participants who met the different criteria were similar for participants infected with HIV-1 only and those infected with both HIV-1 and HIV-2 (see the Supplementary Appendix). Participants in whom AIDS did not develop during the follow-up period had data right-censored at the date of the last clinical examination. Owing to imbalances in the sex ratio of the enrolled population, analyses were also performed with stratification on the basis of sex. Finally, a Cox proportional-hazards model was applied, adjusting for sex and age at the time of seroconversion. To verify the proportional-hazards assumption, we analyzed log–minus–log plots to rule out any crossing of the curves.

Analysis of CD4+ and CD8+ T-Cell Counts

Both the absolute CD4+ T-cell count and the percentage of CD4+ T cells are reliable immunologic markers of HIV disease progression. In resource-limited settings, the percentages of T-cell populations may be more suitable measures than counts, because of their lower variability and lower sensitivity to specimen handling, participant age, and time of sampling.17,18 Accordingly, we analyzed the percentage of CD4+ and CD8+ T cells. (Absolute T-cell counts are given in Tables S1 and S2 in the Supplementary Appendix.) Two or more measurements of percentages of CD4+ and CD8+ T cells were available for 71 and 55 participants with HIV-1 infection only, respectively, and 24 and 22 participants with both HIV-1 and HIV-2 infection. The percentages and their rates of change since seroconversion were compared among the groups with the use of linear mixed models.

HIV-1 Evolutionary Analysis

HIV-1 diversity, divergence, and differences in selective pressures were investigated in a subgroup of 20 participants with HIV-1 infection only and 12 with both HIV-1 and HIV-2 infection for whom two plasma samples from the asymptomatic stage of infection were available. In identifying participants to serve in these subgroups, the primary selection objective was to minimize variation in time between the two sampling time points (mean [±SD], 38.6±20.3 months for HIV-1 infection only and 36.8±16.8 months for dual infection). Secondary objectives were to minimize variation in the time from seroconversion to first sampling (28.0±15.5 months for HIV-1 infection only and 38.7±17.1 months for dual infection) and to ensure that the first sample was not collected during the acute stage of infection.

The V1–V3 region of the HIV-1 envelope gene (env) was cloned and sequenced as described previously.19 From each sample, 12 clones were sequenced. Maximum-likelihood and Bayesian phylogenies were used for subsequent evolutionary analysis. Diversity was calculated by averaging pairwise tree distances between participant-specific sequences obtained from the same sample time point. Diversity rates, evolutionary substitution rates, and synonymous and nonsynonymous substitution rates were estimated as described in the Supplementary Appendix. Sequences used in this study were deposited into GenBank under the accession numbers HM745935 through HM746598.

Results

Epidemiologic Analysis

Table 1. Table 1. Baseline Characteristics of the Participants, According to Study Group.

In total, 223 participants were infected with HIV-1 after enrollment; 191 were infected with HIV-1 only (161 men and 30 women), and 32 were infected with both HIV-1 and HIV-2 (26 men and 6 women) (Table 1). Among the participants with dual infection, 12 had concomitant dual seroreactivity and 20 had HIV-2 seroreactivity before dual seroreactivity occurred. Dual infection and concomitant dual seroreactivity could have occurred by means of three potential infection scenarios: HIV-1 infection preceding dual infection, HIV-2 infection preceding dual infection, or simultaneous HIV-1 and HIV-2 infection. In the cohort and apart from the 32 participants with dual infection described above, 1 participant was infected with HIV-1 after enrollment but before conversion to dual seropositivity. This participant was excluded from the study because no conclusions could be drawn about this group from 1 person and because of the aim of the study: to investigate whether HIV-2 infection could affect the rate of HIV-1 disease progression during the complete course of HIV-1 infection (including the important acute phase, during which the level of infection is established).

The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with both HIV-1 and HIV-2 infection and 68 months (95% CI, 60 to 76) in participants with HIV-1 infection only (P=0.003 by the log-rank test) (Fig. S1 in the Supplementary Appendix). Participants with HIV-1 infection only and those with dual infection did not differ significantly in age (P=0.10 by a two-tailed Student's t-test) or sex (P=0.61 by a two-tailed Fisher's exact test), and a similar proportion of participants in each of the two groups had data right-censored during the study period (Supplementary Appendix). Stratification according to sex showed a slightly more pronounced difference in the time to AIDS between the groups (P=0.001 by the log-rank test). The adjusted hazard ratio for progression to AIDS among HIV-1–infected participants versus participants with dual infection was 2.81 in a Cox proportional-hazards model controlling for age and sex (95% CI, 1.55 to 5.09; P<0.001 by the Wald test).

Figure 1. Figure 1. Kaplan–Meier Analysis of Time to the Development of AIDS, According to Study Group.

Tick marks indicate participants with censored data. Asterisks indicate the time point in each group when five participants are still at risk for the development of AIDS.

To evaluate the effect of the order of infection (with HIV-2 preceding or being simultaneously recorded with HIV-1), we stratified the dual-infection group into the 20 participants with HIV-2 seroreactivity preceding dual seroreactivity and the 12 with simultaneous HIV-1 and HIV-2 seroreactivity recorded first. Kaplan–Meier analysis showed that the 20 participants who had HIV-2 seroreactivity first had a longer time to AIDS (median, 129 months [95% CI, 93 to 165]) than participants with HIV-1 infection only (P=0.007 by the log-rank test) (Figure 1). Even though the time to AIDS in the group with dual infection and simultaneous HIV-1 and HIV-2 seroreactivity recorded first was intermediate (88 months; 95% CI, 69 to 106), this time did not differ significantly from that in either the group with dual infection and HIV-2 seroreactivity first (P=0.50 by the log-rank test) or the group with HIV-1 infection only (P=0.13 by the log-rank test). The hazard ratio for progression to AIDS (after controlling for age and sex) was 3.12 (95% CI, 1.52 to 6.41; P=0.002 by the Wald test) for HIV-1 infection only as compared with dual infection with HIV-2 seroreactivity first and was 2.27 (95% CI, 0.90 to 5.68; P=0.08 by the Wald test) for HIV-1 infection only as compared with dual infection with simultaneous HIV-1 and HIV-2 seroreactivity recorded first. The hazard ratio for dual infection with simultaneous HIV-1 and HIV-2 seroreactivity recorded first as compared with dual infection with HIV-2 seroreactivity first was 1.37 (95% CI, 0.45 to 4.17; P=0.58 by the Wald test).

CD4+ and CD8+ T Cells

Table 2. Table 2. CD4+ or CD8+ T-Cell Percentage of the Total Lymphocyte Count, According to Study Group.

We used a full-factorial mixed model with time since seroconversion as the covariate to compare the extrapolated level at seroconversion and rate of decline in CD4+ T-cell percentage in participants infected with HIV-1 only and those infected with both HIV-1 and HIV-2. The rate of decline in CD4+ T-cell percentage was similar with HIV-1 infection only and dual infection, with an average decline of 1.2% per year (P=0.36, with the use of a mixed model with interaction term removed). However, the CD4+ T-cell percentage was significantly higher in participants with dual infection (31.3%) than in those with HIV-1 infection only (23.3%) (P<0.001) (Table 2). A stratified analysis showed similar decreases in CD4+ T-cell percentages in the group with dual infection and simultaneous HIV-1 and HIV-2 seroreactivity recorded first and the group with dual infection and HIV-2 seroreactivity first. The latter group had, however, a significantly higher CD4+ T-cell percentage (32.3%) than those with HIV-1 infection only (P<0.001). The group with dual infection and simultaneous HIV-1 and HIV-2 seroreactivity recorded first showed an intermediate CD4+ T-cell percentage (28.1%), with no significant difference from either the group infected with HIV-1 only or the group with dual infection and HIV-2 seroreactivity first (Table 2). Next, we examined differences in CD8+ T-cell percentages over time, finding a slower increase in CD8+ T-cell percentages among participants with dual infection (1.5% per year) than among those with HIV-1 infection only (3.0% per year, P=0.03) (Table 2). A significant difference was also found between HIV-1 infection only and dual infection with HIV-2 seroreactivity first (P=0.002) but not between HIV-1 infection only and dual infection with simultaneous HIV-1 and HIV-2 seroreactivity recorded first (P=0.52).

Since the percentages and rates of change in T-cell populations may differ among disease stages, we also analyzed T-cell counts during the asymptomatic stage of infection (defined as CD4+ T-cell counts >200 or >14% of the total). As found in the analysis of the complete data set, the rate of decline in CD4+ T-cell percentages was similar among participants with HIV-1 infection only and those with dual infection, with an average decline of 0.8% per year (P=0.20, with the use of a mixed model with interaction term removed). The CD4+ T-cell percentage at the extrapolated level at seroconversion was significantly higher with dual infection (30.1%) than with HIV-1 infection only (24.3%) (P=0.005) (Table S3 in the Supplementary Appendix). The stratified analysis showed rates of decreasing CD4+ T-cell percentages that were similar with dual infection with simultaneous HIV-1 and HIV-2 seroreactivity recorded first and dual infection with HIV-2 seroreactivity first. Again, the latter group had a significantly higher CD4+ T-cell percentage (31.0%) than the group infected with HIV-1 only (P=0.003), whereas the group with dual infection and simultaneous HIV-1 and HIV-2 seroreactivity recorded first had an intermediate percentage, which did not differ significantly from that in either the HIV-1–only group or the group with dual infection and HIV-2 seroreactivity first (Table S3 in the Supplementary Appendix).

Whereas CD8+ T-cell percentages differed significantly over time (i.e., throughout the stages of infection) between the group with HIV-1 infection only and the group with dual infection, there was no significant between-group difference in CD8+ percentages during the asymptomatic stage of infection (P=0.09) (Table S3 in the Supplementary Appendix). However, the rate of increase in CD8+ T-cell percentages was greater with HIV-1 infection only (2.7% per year) than with dual infection with HIV-2 seroreactivity first (0.9% per year, P=0.02) (Table S3 in the Supplementary Appendix). The differences in the changes in CD8+ T-cell percentages prompted us to analyze differences in the immune activation markers β2-microglobulin and neopterin; however, we did not find any significant differences between the participants infected with HIV-1 only and those infected with both HIV-1 and HIV-2 (see the Supplementary Appendix).

Molecular Evolution of HIV-1

HIV-1 evolution is characterized by high mutation rates, rapid viral turnover, and high recombination rates. The evolution can be quantified by diversity (the genetic variation at a given time point) and divergence (the genetic distance to a reference point, e.g., a founder strain). Several studies have presented evidence of a positive correlation between diversity and time from seroconversion during the asymptomatic stage of infection.21-23 HIV-1 diversity has also been positively correlated with viral load and viral fitness.24,25 The rate of divergence of HIV-1 has been shown to be relatively constant (reflected by a linear increase in divergence) during the asymptomatic stage of infection.22,26 Studies comparing divergence rates with disease progression rates show conflicting results.26,27

Figure 2. Figure 2. Disease Progression and Evolution of HIV-1 Diversity.

Panel A shows the epidemiologic estimates of the time to the development of AIDS (time to AIDS) in participants with HIV-1 infection only (68 months) and those with HIV-1 and HIV-2 infection (dual infection) (104 months). The difference between the study groups was 36 months. Panel B shows the data from models on the rate of evolution of HIV-1 genetic diversity (the genetic variation at a given time point, as measured in substitutions per site) for HIV-1 infection only and dual infection. The indicated diversity threshold (as measured in substitutions per site) for development of AIDS is based on the 68-month time-to-AIDS estimate for participants with HIV-1 infection only (dashed horizontal line). We estimated the time to reach that threshold in participants with dual infection by using the global mean diversity rate (1.75×10–3 substitutions per site per year) to extrapolate from the mean diversity among participants with dual infection to the diversity threshold. For the time to AIDS in participants with dual infection, both the maximum-likelihood estimate (104.93 months) and the Bayesian estimates (104.95 months) were close to the epidemiologic estimate (104 months) (see Table S6 in the Supplementary Appendix).

Since maximum-likelihood and Bayesian analyses showed high concordance (Tables S5 and S6 in the Supplementary Appendix), we present only maximum-likelihood estimates here. The average increase in HIV-1 sequence diversity over time was similar in participants with HIV-1 infection only and those with dual infection, with an average of 1.75×10−3 substitutions per site per year (P=0.81 by the t-test). At similar time points after seroconversion, the diversity was significantly lower among participants with dual infection (5.67×10−3±1.61×10−3 substitutions per site) than among those with HIV-1 infection only (11.04×10−3±1.28×10−3 substitutions per site; P=0.01 by the t-test) (Figure 2).

Despite detailed evolutionary analyses, we found no significant differences between the HIV-1–infection group and the dual-infection groups in the rates of HIV-1 divergence or synonymous or nonsynonymous substitutions (Table S5 in the Supplementary Appendix).

Discussion

In the present study, we found that HIV-2 has an inhibitory effect on the rate of HIV-1 disease progression in vivo. This inhibition was evident in the time to AIDS, at the cellular level of the immune system, and at the molecular level of HIV-1 evolution. Our observations are built on data from participants who were infected with HIV-1 after enrollment in a cohort with a long follow-up duration (approximately 20 years). These observations are supported by experimental studies involving the macaque model, which have shown inhibition against both immunosuppression and disease induced by infection with the simian immunodeficiency virus as a result of contemporaneous HIV-2 infection.28,29

Our observation of significantly higher CD4+ T-cell percentages in participants with dual infection than in those with HIV-1 infection only, in combination with similar rates of decline in CD4+ T-cell percentages, indicates that determinants of differences in disease outcome may be related to events in early infection. The slower increase in CD8+ T-cell percentages over time in participants with dual infection than among participants infected with HIV-1 only suggests that alteration in cellular immune activation may contribute to the disease outcome. Indeed, there have been several reports of a positive correlation between CD8+ T-cell activation and HIV-1 disease progression rate.30,31 Cavaleiro and colleagues investigated the immunologic effects of HIV-2 envelope glycoprotein 105 on anti-CD3–stimulated peripheral-blood mononuclear cells and found that glycoprotein 105 had a higher inhibitory effect against T-cell proliferation than the HIV-1 envelope glycoprotein 120.32 Furthermore, it has been suggested that the Nef protein of HIV-2, but not of HIV-1, may down-modulate the TCR-CD3 complex and thereby suppress T-cell responsiveness to activation.33

HIV-2 could also continuously alter the expression of cellular factors that affect the susceptibility of the uninfected cellular environment. In vitro studies have shown that HIV-2 infection generates higher levels of beta-chemokines (the natural ligands of the HIV coreceptor CCR5) in peripheral-blood mononuclear cells and that this can inhibit HIV-1 infection and replication.10-12,34 Zheng and colleagues found high frequencies of cross-reactivity between samples of persons with single HIV-1 infection and those with single HIV-2 infection when investigating heterologous T-cell responses.35 They also found that persons with HIV-1 infection only who had a response to the HIV-2 Gag protein had lower HIV-1 plasma viral loads than those without this cross-reactivity. A second study by this group showed this to be evident in persons with dual infection as well.36 Antibodies elicited by HIV-2 that cross-neutralize HIV-1 have been described.37,38 Hence, humoral HIV-2 immune responses could also play a role in controlling the rate of HIV-1 disease progression in persons with dual infection.

HIV-1 diversity has been positively correlated with HIV-1 replication efficiency and the rate of progression to AIDS.25,39 The debated diversity threshold theory assumes that AIDS develops when diversity exceeds a critical threshold that varies among people.23 The high level of diversity seen at the onset of AIDS may also be a consequence of the disease progression rather than a cause of disease. Our observation that HIV-1 diversity was significantly lower in participants infected with both HIV-1 and HIV-2 than in those infected with HIV-1 only at similar time points after HIV-1 infection, while the rates of increase in diversity were similar, supports the hypothesis that slower disease progression may be related to inhibitory effects early in HIV-1 infection. Such inhibitory effects would result in a lower initial diversity and a longer asymptomatic stage before the diversity threshold is reached. As reported above, the average time to AIDS was 68 months in participants infected with HIV-1 only, at which time the estimated mean diversity was 13.52×10−3 substitutions per site (Table S6 in the Supplementary Appendix). Participants with dual infection were estimated to have the same mean diversity after 105 months, close to the average observed time to AIDS of 104 months (Figure 2). The strong correlation between diversity and time to AIDS was seen regardless of phylogenetic approach (maximum likelihood or Bayesian) (Table S6 in the Supplementary Appendix). Thus, the mean diversity threshold was almost identical for participants infected with both HIV-1 and HIV-2 and those infected with HIV-1 only, indicating that diversity evolution can be used as a clinical marker for the rate of disease progression.

In summary, we found that participants with dual infection in whom the HIV-2 infection preceded the HIV-1 infection had a longer time to AIDS than participants infected with HIV-1 only. The slower disease progression was reflected by higher levels of CD4+ T-cells in participants with dual infection than in those with HIV-1 infection alone at similar time points and different kinetics in levels of CD8+ T-cells. Phylogenetic analysis revealed differences in HIV-1 molecular evolution between dual and single infection, with lower viral diversity associated with dual infection. Further investigation of the interplay between HIV-1 and HIV-2 and of any systemic immunologic effects of a contemporaneous HIV-2 infection on HIV-1 pathogenesis could reveal new and critical mechanisms important for the development of future HIV-1 interventions.

Funding and Disclosures

Supported by grants from the Swedish International Development Cooperation Agency–Swedish Agency for Research Cooperation with Developing Countries, the Swedish Research Council, the Crafoord Foundation, the Royal Physiographic Society, the Lars Hierta Memorial Foundation, Konsul Thure Carlsson Fund for Medical Research, the Tegger Foundation, the Medical Faculty of Lund University, and the regional agreement on medical training and clinical research between Region Skåne and the Medical Faculty of Lund University.

We thank Françoise Barré-Sinoussi, Mattias Höglund, Mattias Mild, and Lisa Esbjörnsson-Klemendz for critically reviewing an earlier version of the manuscript; and Babetida N'Buna, Aquilina Sambu, Eusebio Ieme, Isabel da Costa, Jacqueline Pereira Barreto, Ana Monteiro Watche, Cidia Camara, Braima Dabo (deceased), Carla Pereira, Julieta Pinto Delgado, Leonvengilda Fernandes Mendes, Ana Monteiro, Ansu Biai, Fransisco Dias, Anders Nauclér, Gunnel Biberfeld, Sören Andersson, Helen Linder, Wilma Martinez-Arias, Pär-Ola Bendahl, and staff at the Swegene Center for Integrative Biology at Lund University for their contributions to this work.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Esbjörnsson and Månsson contributed equally to this article.

Author Affiliations

From the Department of Experimental Medical Science, Section of Molecular Virology (J.E., P.M.), the Department of Clinical Sciences, Section of Oncology, Lund University and Skåne University Hospital (A.K.), the Department of Statistics, Lund University School of Economics and Management (P.-E.I.), the Department of Laboratory Medicine Lund, Division of Medical Microbiology (M.J., E.M.F.), and the Department of Clinical Sciences, Division of Infection Medicine (H.N.), Lund University, Lund; the Department of Clinical Sciences Malmö, Infectious Diseases Research Unit (F.M.), and the Department of Laboratory Medicine Malmö (P.M.), Lund University, Malmö; and the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm (S.N., M.J.) — all in Sweden; and the National Public Health Laboratory, Bissau, Guinea-Bissau (A.J.B., Z.J.S.).

Address reprint requests to Dr. Esbjörnsson at the Section of Molecular Virology, Department of Experimental Medical Science, Lund University, BMC C13 Sölvegatan 19, SE-22184 Lund, Sweden, or at .

Supplementary Material

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    Figures/Media

    1. Table 1. Baseline Characteristics of the Participants, According to Study Group.
      Table 1. Baseline Characteristics of the Participants, According to Study Group.
    2. Figure 1. Kaplan–Meier Analysis of Time to the Development of AIDS, According to Study Group.
      Figure 1. Kaplan–Meier Analysis of Time to the Development of AIDS, According to Study Group.

      Tick marks indicate participants with censored data. Asterisks indicate the time point in each group when five participants are still at risk for the development of AIDS.

    3. Table 2. CD4+ or CD8+ T-Cell Percentage of the Total Lymphocyte Count, According to Study Group.
      Table 2. CD4+ or CD8+ T-Cell Percentage of the Total Lymphocyte Count, According to Study Group.
    4. Figure 2. Disease Progression and Evolution of HIV-1 Diversity.
      Figure 2. Disease Progression and Evolution of HIV-1 Diversity.

      Panel A shows the epidemiologic estimates of the time to the development of AIDS (time to AIDS) in participants with HIV-1 infection only (68 months) and those with HIV-1 and HIV-2 infection (dual infection) (104 months). The difference between the study groups was 36 months. Panel B shows the data from models on the rate of evolution of HIV-1 genetic diversity (the genetic variation at a given time point, as measured in substitutions per site) for HIV-1 infection only and dual infection. The indicated diversity threshold (as measured in substitutions per site) for development of AIDS is based on the 68-month time-to-AIDS estimate for participants with HIV-1 infection only (dashed horizontal line). We estimated the time to reach that threshold in participants with dual infection by using the global mean diversity rate (1.75×10–3 substitutions per site per year) to extrapolate from the mean diversity among participants with dual infection to the diversity threshold. For the time to AIDS in participants with dual infection, both the maximum-likelihood estimate (104.93 months) and the Bayesian estimates (104.95 months) were close to the epidemiologic estimate (104 months) (see Table S6 in the Supplementary Appendix).