Skip Navigation LinksHome > May 21, 2004 - Volume 18 - Issue 8 > Differences in disease progression in a cohort of long-term...
AIDS:
Basic Science

Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection

Rodés, Berta; Toro, Carlos; Paxinos, Ellena; Poveda, Eva; Martinez-Padial, Manuelb; Benito, José Miguel; Jimenez, Victoria; Wrin, Terrib; Bassani, Sylvina; Soriano, Vincent

Free Access
Article Outline
Collapse Box

Author Information

From the Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain, aVirologic Inc, South San Francisco, California, USA, and the bMicrobiology Department, Hospital Carlos III, Madrid, Spain.

Correspondence to V. Soriano, Calle Nueva Zelanda 54, 4B, Madrid 28035, Spain.

Received: 17 December 2003; revised: 22 February 2004; accepted: 16 March 2004.

Collapse Box

Abstract

Background: It is unclear whether resistance to immunologic damage in long-term non-progressors (LTNP) will last indefinitely or whether it merely represents the extreme of a Gaussian distribution, and therefore progression will occur eventually.

Patients and methods: A cohort of 19 LTNP was established in 1997. Plasma viraemia and CD4 cell counts were measured two to three times each year until 2003. Analyses of nef and vpr viral genes, CCR5 genotypes, co-receptor tropism, viral replication capacity, and immunological parameters were performed.

Results: Twelve subjects (non-progressors, NP) showed stable CD4 cell counts over the 6-year follow-up, while seven (slow progressors, SP) showed a trend towards progressive CD4 cell depletion; however, only three SP experienced significant CD4 cell count declines. All SP had detectable plasma HIV-RNA (median 1118 copies/ml). In contrast, five of 12 NP had always undetectable viraemia. Only one patient showed a deletion in nef. The vpr R77Q change was recognized in seven patients. All patients were infected with R5 viruses. The virus replicative capacity was reduced in all tested individuals (range 5–93%). None of the patients was homozygous for the delta-32 CCR5 genotype, which was found in heterozygosis in three. CD8 T-cell activation was low in all but three individuals, all of whom had detectable viraemia and showed progressive CD4 cell depletion. Cytotoxic T lymphocyte responses were similar to those found in a control group of HIV progressors.

Conclusions: A substantial proportion of LTNP show low-level virus replication and progressive loss of CD4 T cells over time. Progressive immunologic damage seems to be directly associated with some degree of virus replication and T-cell activation.

Back to Top | Article Outline

Introduction

The course of HIV-1 infection varies greatly among infected patients. In a small proportion of individuals (1–5%), HIV-1 seems to be less pathogenic and there is no apparent progression. By definition, these long-term non-progressors (LTNP) remain asymptomatic, with CD4 cell counts > 500 × 106 cells/l and low or undetectable viral load, in the absence of any antiretroviral therapy. The cause of the lack of progression in these persons is unclear, but it seems to result from the interaction between multiple factors linked to either the virus or the host [1]. The recognition of what factors are the main determinants for protection against HIV-1 disease progression is of great interest, since it may allow new treatment strategies to be designed.

Strain attenuation has been highlighted as one of the main viral factors accounting for the lack of HIV-1 disease progression. A defective nef gene may impair virus replication, as demonstrated in a cluster of transfusion-infected individuals from the Sydney Blood Bank Cohort [2]. On the other hand, a R77Q change in the vpr gene reduces dramatically cellular apoptosis, which could influence disease progression [3]. Critical changes at other HIV-1 genes such as vif, vpu or env may also account for the lack of progression in some HIV-infected persons [4,5]. Finally, T-tropic (X4) strains have been linked to increased cytopathogenicity resulting in enhanced T-cell depletion which is lower for M-tropic (R5) viruses [6].

Among host related factors, some mutations in cellular HIV co-receptor genes have been associated with slower disease progression, as result of an impairment in virus attachment and infectivity [7]. Disease progression is also influenced by the host immune response. HIV-specific cytotoxic T lymphocytes (CTL) play an important role in the control of virus replication, but their relative contribution in LTNP is still uncertain [8]. The role of a limited immune activation [9] or certain MHC haplotypes in HIV-1 disease progression remains also unclear [10,11]. Whether all of these factors may occasionally result in a truly protective status against HIV-1 disease progression, or whether they merely delay disease progression is not known. Evidence in favor of further damage has been reported recently in small series of LTNP followed for long periods of time [12,13], but this does not exclude the possibility that infection could be non-pathogenic in some individuals.

Here we describe the main features of a cohort of LTNP established in 1997 and present longitudinal virologic and inmunologic follow-up for a 6-year period.

Back to Top | Article Outline

Patients and Methods

Study population

A cohort of 19 patients with evidence of non- progressive HIV-1 infection was established in 1997 at our institution, a reference HIV/AIDS center located in Madrid. All patients had serologically proven HIV-1 infection for at least 10 years, repeated CD4 cell counts > 500 × 106 cells/l, and no prior history of HIV-related symptoms, in the absence of any antiretroviral therapy. Most of these individuals had been exposed to HIV-1 before 1985 or 1987, when they first tested positive for HIV-1 antibodies. One subject was known to be HIV-1 seropositive since 1979, after testing retrospectively sera stored from that time. All of these individuals have been prospectively followed every 4–6 months since January 1997. The last clinical and laboratory assessment was performed in December 2002. The bDNA assay (Quantiplex v3.0, Bayer, Barcelona, Spain), which has a lower detection limit of 50 HIV RNA copies/ml, was used for measuring plasma viraemia, while the CD4 cell count was determined by flow cytometry using specific mAb (Coulter, Barcelona, Spain).

Back to Top | Article Outline
Genetic analyses

Proviral DNA extracted from peripheral blood mononuclear cells (PBMC) was used to amplify nef and vpr genes by nested PCR. Primers and conditions were as described previously [3,14]. DNA sequencing analysis of the amplified product was performed using an automated sequencer (ABI 3100, Applied Biosystems, Palo Alto, California, USA). DNA and encoded protein sequences were aligned using ClustalX software. Sequences generated in this study were submitted to GenBank and given the accession numbers AY444304–AY444318 for nef and AY444319–AY444336 for vpr.

The presence of the Δ32-CCR5 allele was determined by PCR in genomic DNA extracted from PBMC. Assay conditions have been described elsewhere [7]. PCR products were analysed in a 2% agarose gel.

Back to Top | Article Outline
Virus replicative capacity and viral tropism

The replicative capacity of HIV-1 was measured by a single-cycle phenotypic assay (Phenosense, Virologic Inc., South San Francisco, California, USA) [15]. Results were expressed as percentage of luciferase activity generated by each patient recombinant vector relative to that generated by a wild-type reference virus. Values ranged from 5% (low replicative fitness) to 120% (high replicative fitness).

Viral co-receptor tropism was determined using a modification of the Phenosense assay. Recombinant viruses were tested for their ability to infect CD4/CXCR5 and/or CD4/CXCR4 cells. Tropism was verified by assessing the ability of a CCR5- and/or CXCR4-antagonist to block HIV-1 infection.

Back to Top | Article Outline
Levels of activation in T cell subsets

CD4 and CD8 T cells as well as their naive (CD45RA62L) and memory (CD45RO) subsets were assessed in fresh whole blood collected longitudinally from these patients using a panel of mAb (Beckman-Coulter, Miami, Florida, USA) and four-colour flow cytometry. The intensity of expression of the CD38 activation marker on CD8 T cells was measured using a quantitative dual-colour flow cytometry assay (Cellquant CD38/CD8-PE, Biocytex, Marseille, France).

Back to Top | Article Outline
Measurement of HIV specific cytotoxic CD8 T lymphocytes

Levels of HIV-specific CTL were measured by four-colour flow cytometry, using an interferon (IFN)-γ production assay in response to 125 optimal peptides divided into five pools (Gag, Pol, Env, Nef and Reg proteins). The results were recorded as the percentage of CD8 T cells producing IFN-γ and expressing the early activation marker CD69. We defined the total CTL response as the sum of individual responses to the five pools. All tests were performed at one time point in samples collected from all LTNP in 2001. The results were compared with those obtained in a control group of comparable drug-naive HIV-infected subjects showing progressive HIV infection (mean viral load and CD4 cell counts of 4.3 ± 1 log10 HIV RNA copies/ml and 534 ± 246 × 106 cells/l, respectively).

Back to Top | Article Outline
Statistical analyses

The main results are described in absolute values and percentages. Changes in CD4 T-cell counts and plasma HIV-RNA over time were assumed to be linear and regressions were calculated accordingly. Statistical analyses were performed using the SSPS software version 10. All P values were two-sided. Significance was established for P < 0.05.

Back to Top | Article Outline

Results

Demographics and clinical follow-up

Most individuals in this cohort were first identified as HIV-1 seropositive in 1986 and 1987, and since then have been on regular follow-up at our institution, with periodic controls two to three times per year. They represent a unique subpopulation (approximately 1%), among a total of around 2100 different HIV-infected individuals on regular follow-up at our institution. Eleven (57.8%) of the 19 patients were male. All but one (97.7%) were former injecting drug users. Their mean age was 40.4 years and the mean length of proven HIV-1 infection was 14.7 years in 1997, at the time of cohort establishment. Their mean alcohol intake was 106 g/day (range 0–300 g/day). All were seropositive for hepatitis C virus (HCV) antibodies and 17 patients had markers of prior hepatitis B virus (HBV) exposure. One subject had persistent HBV surface antigen and therefore had been diagnosed as having chronic hepatitis B. Four patients cleared HCV while the rest maintained positive HCV RNA. Interestingly, those four HCV PCR-negative patients belonged to the non-progressor (NP) group.

Figs 1 and 2 show the evolution of CD4 T cell counts and plasma viraemia in all 19 LTNP of this cohort during the period between January 1997 and December 2002. Twelve subjects showed stable CD4 cell counts (Table 1), and were classified as NP, while seven subjects showed a reduction in the number of these cells and were classified as slow progressors (SP). The median loss of CD4 T cells in SP was 64 × 106 cells/l per year (Table 2). In three of these SP, the slope of the CD4 decay was statistically significant. All seven SP had detectable plasma viraemia with an average of 1118 HIV RNA copies/ml. In contrast, five out of 12 NP had undetectable viral load at all time points (Table 1). Overall, the mean plasma HIV RNA in NP was 85 copies/ml. The difference in viral load between NP and SP was statistically significant (P = 0.017).

Fig. 1
Fig. 1
Image Tools
Fig. 2
Fig. 2
Image Tools
Table 1
Table 1
Image Tools
Table 2
Table 2
Image Tools

There was no association between the degree of progression (NP or SP) and any of the variables associated with disease progression (e.g., age, sex and high alcohol intake) or with chronic hepatitis B and/ or C.

Back to Top | Article Outline
Genetic analyses

All 19 LTNP carried HIV-1 subtype B strains. Analysis of nef showed that all but one had a functional nef gene, with no alterations or defects in their functional domains (Table 3). In this patient (number 3) molecular analysis revealed a deletion of 199 bp. This deletion removed the highly conserved acidic domain, (PXX)4 and PKC motifs, and placed downstream sequences out of frame, which resulted in a premature stop codon. This patient has maintained stable CD4 T-cell counts for more than 16 years. No duplications of the nuclear factor (NF)-κB binding elements that could compensate this deletion were found. All of the patients with a complete nef gene showed some amino acid features (T15, N51, H102, L170 and E182) which previously have been associated with non-progressive HIV-1 infection. In fact, their ‘Nef progression score’ was within the range assigned by others [16] to NP. However, no differences were observed when comparing NP and SP in this study.

Table 3
Table 3
Image Tools

Genetic analysis of vpr showed that all 19 LTNP carried a functional gene. The Vpr peptide was 96 amino acids long in all but one individual, who had an insertion of three amino acids at the C-terminal end. The R77Q change was found in seven (36.8%) patients. There were no significant differences when comparing NP and SP: 4/11 (33%) and 3/7 (42.5%), respectively. However, patients with detectable plasma viraemia and/or higher CD38 expression tended to show R77Q more frequently than patients with undetectable viral load and minimal immune activation.

No patient was homozygous for the Δ32 CCR5 genotype, which was found in heterozygosity in only three subjects (nos. 14, 15 and 17). All patients with Δ32 CCR5 were SP (Table 3).

Back to Top | Article Outline
Virus replicative capacity and co-receptor usage

The replicative capacity (RC) could be measured in viruses from only seven individuals (three NP and four SP) from whom samples were available. Overall, RC values were lower in LTNP with respect to wild-type viruses taken as controls. However, there was a wide variability in the RC among isolates from LTNP, ranging from 5% to 93%. The median RC values were 40% in NP and 74.5% in SP.

Viral co-receptor tropism was examined in the seven patients tested for RC. All individuals were infected with R5 viruses. However, longitudinal samples collected from one patient (number 15) belonging to the SP group showed a shift from exclusively R5 viruses at baseline to a mixed X4/R5 virus population in samples collected on follow-up. This switch preceded a CD4 T-cell decline of 80 × 106 cells/l per year. Interestingly, virus tropism characterization of the two most recent blood specimens collected from this patient show only R5 viruses.

Back to Top | Article Outline
Activation of T-cell subsets

Levels of CD8 T-cell activation were low in all LTNP but three, all of whom had detectable viraemia and showed a progressive CD4 T-cell decline. There was a trend towards an association between T-cell activation and disease progression. Patients belonging to the SP group showed slightly higher activation of CD8 T cells in respect to NP, although the difference did not reach statistical significance (P = 0.08), probably due to the small size of the study population (Table 3). Activation of CD4 T cells was also lower in LTNP than in controls, but there were no significant differences between NP and SP.

Back to Top | Article Outline
HIV specific CTL responses

The mean number of peptide pools to which patients responded was similar (4 ± 1) in LTNP and a group of controls (HIV progressors). For each pool of peptides, a positive CTL response was detected in LTNP and controls, respectively: 93% and 86% to Gag; 92% and 68% to Pol; 93% and 81% to Env; 87% and 100% to Nef; 40% and 47% to regulatory peptides.

There were no differences in the level of CTL responses against each pool, nor in the level of total responses between LTNP and controls: Gag, 0.52% versus 0.82%; Pol, 0.37% versus 0.43%; Env, 0.32% versus 0.31%; Nef, 0.46% versus 0.53%; Reg, 0.07% versus 0.14%; total, 1.84% versus 2.23%. In both groups, the peptide pool that contributed most to the total CTL response was Gag (28.7% in LTNP versus 32.8% in controls), followed by Nef (23.9% versus 28.7%), Env (22.2% versus 17%), Pol (21.3% versus 13%) and lastly regulatory peptides (3.7% versus 8.2%), respectively. Finally, there were no significant differences in the CTL response when comparing NP and SP.

Back to Top | Article Outline

Discussion

We have described the main features and subsequent outcome of a cohort of 19 LTNP established in 1997. Most of these individuals were first recognized as HIV-1 seropositive in 1985 and 1987, although we have evidence of infection in one of them since 1979. Thus, at the time of cohort establishment all of these subjects had been infected with HIV-1 for more than 10 years. An important finding in our study was the recognition of a different outcome in the study population during the subsequent 6 years of follow-up. Twelve subjects (NP) have remained asymptomatic with stable CD4 T-cell counts while the other seven (SP) have experienced a significant decline of these cells. A similar delayed diminution of CD4 T cells has been reported in other LTNP [12,13]. We could not find any association of this phenomenon with some of the potential cofactors such as age, sex, alcohol intake or other infectious agents, such as hepatitis viruses.

The majority of individuals assigned to the group of NP had undetectable viral load at all time points. On the contrary, all subjects showing slow progressive disease had detectable levels of viraemia. Thus, the ability of the virus to replicate with more or less efficiency was clearly one critical determinant of the distinct outcome seen in this cohort of LTNP, as has been suggested by others [17,18]. Although the virus replicative capacity was reduced in almost all of the patients, slightly lower values were observed in NP than in SP. These findings are in agreement with a causal relationship between viral replication and CD4 T-cell depletion. Whether it results from direct cell killing by the virus and/or from indirect mechanisms such as immune activation is open to debate [19]. Most subjects in this cohort of LTNP showed low T-cell activation, which tended to be lower in NP than in SP. Thus, it might be argued that low immune activation could have contributed to preserve these patients from CD4 T-cell depletion.

Specific HIV CTL responses are important in restricting viral replication and probably also in delaying disease progression. However, in our study we did not find differences in the level of CTL responses when comparing LTNP with a control group of drug-naive HIV progressors. Thus, our findings do not support a critical role of CTL responses in halting HIV progression. If relevant, qualitative parameters within the CTL response could be the main determinants of HIV control, as suggested by others [20].

Non-syncytium inducing strains seem to be less deleterious to the host immune system [21] and along with a low replicative capacity, may determine slower progression of HIV disease [22]. In our cohort, six out of seven LTNP maintained R5 viruses during the entire follow-up. The single patient who showed a shift from R5 to mixed R5/X4 viruses at some point, suffered a coincident rapid loss of CD4 T lymphocytes. The emergence of viral variants capable of using an expanded range of coreceptors most probably explained this adverse outcome in this individual.

The Δ32-CCR5 allele seems to provide a continuous protective effect during the course of HIV-1 infection, reducing the risk of disease progression by 31% when present in heterozygosity [23]. None of our patients presented this allele in homozygosis and only three carried the Δ32 deletion in heterozygosis. Since all of them belonged to the SP group, our findings do not support a critical role of CCR5 as cause of LTNP. The protection by the CCR5 delta phenotype is lost when the infecting strain is able to induce syncytia [24]. Interestingly, one of our patients with the Δ32 deletion was the subject who showed a virus with mixed CCR5/CXCR4 tropism. At the time of its appearance, the patient showed a significant CD4 T-cell depletion, perhaps indirectly reflecting a protective effect of Δ32-CCR5.

We could not find any other virological feature in these LTNP which could distinguish those showing slow progression and those without any progression at all. Large deletions in nef are rarely present in HIV isolates from infected persons, although they seem to be more common in LTNP [25,26]. Only one of our patients presented a major deletion that rendered a non-functional nef gene. Moreover, specific amino acid changes in Nef, which have been associated with LTNP [16], did not differ among NP and SP. Likewise, we did not find differences between vpr genes from NP and SP. The change R77Q was present in 33% and 42% of NP and SP, respectively. These percentages are clearly below those reported originally among LTNP, which were in the range of 80% [3]. Interestingly, most LTNP with detectable viraemia in our cohort presented the R77Q change, and it could be hypothesized that the presence of this mutation might have ameliorated T-cell destruction in those individuals despite them harbouring detectable viral load.

In summary, LTNP seem to be a heterogeneous small subset of HIV-1 infected individuals. No unique viral or host factors explain the absence of disease progression. Even very low levels of HIV replication seem to result in progressive CD4 T-cell depletion, although in these patients it may take decades to become manifest. Whether this applies to all LTNP or whether a subset of them will maintain their CD4 T-cell numbers indefinitely is unclear.

Back to Top | Article Outline

Acknowledgements

The authors thank J. Gonzalez-Lahoz for his continuous support.

Sponsorship: Supported in part by grants from Comunidad Autónoma de Madrid, Asociación Investigación y Educación en SIDA, FIPSE, and Red de Investigación en SIDA (RIS G03/173).

Back to Top | Article Outline

References

1. Saksena N, Wang B, Dyer W. Biological and molecular mechanisms in progression and non-progression of HIV disease. AIDS Rev 2001, 3:133–144.

2. Deacon N, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker D, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 1995, 270:988–991.

3. Lum JJ, Cohen OJ, Nie Z, Weaver JG, Gomez TS, Yao X-J, et al. Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. J Clin Invest 2003, 111:1547–1554.

4. Yamada T, Iwamoto A. Comparison of proviral accessory genes between long-term nonprogressors and progressors of HIV type 1 infection. Arch Virol 2000, 145:1021–1027.

5. Alexander L, Weiskoptf E, Greenough T, Gaddis N, Auerbach M, Malim M, et al. Unusual polymorphisms in HIV-1 associated with nonprogressive infection. J Virol 2000, 74:4361–4376.

6. Grivel J, Margolis L. CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue. Nat Med 1999, 5:344–346.

7. Samson M, Libert F, Doranz B, Rucker J, Liesnard C, Farber C, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996, 382:722–725.

8. Hogan C, Hammer S. Host determinants in HIV infection and disease (part I). Ann Intern Med 2001, 134:761–776.

9. McCune JM. The dynamics of CD4 T-cell depletion in HIV disease. Nature 2001, 410:974–979.

10. Migueles S, Sabbaghian M, Shupert W, Bettinotti M, Marincola F, Martino L, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci USA 2000, 97:2709–2714.

11. Hogan C, Hammer S. Host determinants in HIV infection and disease (part II). Ann Intern Med 2001, 134:978–996.

12. Birch M, Learmont J, Dyer W, Deacon N, Zaunders J, Saksena N, Cunningham A, et al. An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC). J Clin Virol 2001, 22:263–270.

13. Greenough T, Sullivan J, Desrosiers R. Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. N Engl J Med 1999, 340:236–237.

14. Wang B, Spira T, Owen S, Lal R, Saksena N. HIV-1 strains from a cohort of American subjects reveal the presences of a V2 region extension unique to slow progressors and non-progressors. AIDS 2000, 14:213–223.

15. Deeks S, Wrin T, Liegler T, Hoh R, Hayden M, Barbour J, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001, 344:472–480.

16. Kirchhoff F, Easterbrook P, Douglas N, Troop M, Greenough T, Weber J, et al. Sequence variations in HIV type 1 Nef are associated with different stages of disease. J Virol 1999, 73:7752–7764.

17. Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen O, Demarest J, et al. Studies in subjects with long-term nonprogressive HIV infection. N Engl J Med 1995, 332:209–216.

18. Candotti D, Costagliola D, Joberty C, Bonduelle O, Rouzioux C, Autran B, et al. Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with virus replication properties and cell tropism. J Med Virol 1999, 58:256–263.

19. Silvestri G, Feinberg M. Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest 2003, 112:821–824.

20. Migueles S, Laborico A, Shupert W, Sabbaghian MS, Rabin R, Hallahan C, et al. HIV-specific CD8+T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature 2002, 3:1061–1068.

21. Blaak H, van't Wout A, Brouwer M, Hooibrink B, Hovenkamp E, Schuitemaker H. In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline. Proc Natl Acad Sci USA 2000, 97:1269–1274.

22. Xiao L, Rudolph D, Owen S, Spira T, Lal R. Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression. AIDS 1998, 12:F137–F143.

23. Mulherin S, O'Brien T, Ioannidis J, Goedert J, Buchbinder S, Coutinho R, et al. Effects of CCR5-D32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection. AIDS 2003, 17:377–387.

24. Schonning K, Joost M, Gram G, Machuca R, Nielsen C, Nielsen J, et al. Chemokine receptor polymorphism and autologous neutralizing antibody response in long-term HIV-1 infection. J Acquir Immune Defic Syndr Hum Retrovirol 1998, 18: 195–202.

25. Mariani R, Kirchhoff F, Greenough T, Sullivan J, Desrosiers R, Skowronski J. High frequency of defective Nef alleles in a long-term survivor with nonprogressive HIV type 1 infection. J Virol 1996, 70:7752–7764.

26. Rhodes D, Ashton L, Solomon A, Carr A, Cooper D, Kaldor J, et al. Characterization of three Nef-defective HIV type 1 strains associated with long-term nonprogression. J Virol 2000, 74:10581–10588.

Cited By:

This article has been cited 53 time(s).

Plos One
Different Immunological Phenotypes Associated with Preserved CD4+T Cell Counts in HIV-Infected Controllers and Viremic Long Term Non-Progressors
Gaardbo, JC; Hartling, HJ; Ronit, A; Thorsteinsson, K; Madsen, HO; Springborg, K; Gjerdrum, LMR; Birch, C; Laye, M; Ullum, H; Andersen, AB; Nielsen, SD
Plos One, 8(5): -.
ARTN e63744
CrossRef
Journal of Medical Virology
Mutations in the nef and vif genes associated with progression to AIDS in elite controller and slow-progressor Patients
Cruz, NVG; Amorim, R; Oliveira, FE; Speranza, FAC; Costa, LJ
Journal of Medical Virology, 85(4): 563-574.
10.1002/jmv.23512
CrossRef
Blood
Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression
Pastori, C; Weiser, B; Barassi, C; Uberti-Foppa, C; Ghezzi, S; Longhi, R; Calori, G; Burger, H; Kemal, K; Poli, G; Lazzarin, A; Lopalco, L
Blood, 107(): 4825-4833.
10.1182/blood-2005-06-2463
CrossRef
Virus Genes
Genetic analysis of the long terminal repeat (LTR) promoter region in HIV-1-infected individuals with different rates of disease progression
de Arellano, ER; Martin, C; Soriano, V; Alcami, J; Holguin, A
Virus Genes, 34(2): 111-116.
10.1007/s11262-006-0054-z
CrossRef
Journal of Virology
Efficient thymopoiesis contributes to the maintenance of peripheral CD4 T cells during chronic human immunodeficiency virus type 2 infection
Gautier, D; Beq, S; Cortesao, CS; Sousa, AE; Cheynier, R
Journal of Virology, 81(): 12685-12688.
10.1128/JVI.01131-07
CrossRef
Virology
In vitro replication capacity of HIV-2 variants from long-term aviremic individuals
Blaak, H; van der Ende, ME; Boers, PHM; Schuitemaker, H; Osterhaus, ADME
Virology, 353(1): 144-154.
10.1016/j.virol.2006.05.029
CrossRef
Journal of Virology
Human immunodeficiency virus type 1 Vpr induces DNA replication stress in vitro and in vivo
Zimmerman, ES; Sherman, MP; Blackett, JL; Neidleman, JA; Kreis, C; Mundt, P; Williams, SA; Warmerdam, M; Kahn, J; Hecht, FM; Grant, RM; de Noronha, CMC; Weyrich, AS; Greene, WC; Planelles, V
Journal of Virology, 80(): 10407-10418.
10.1128/JVI.01212-06
CrossRef
2006 American Control Conference, Vols 1-12
An output-feedback MPC-based scheduling method for enhancing immune response to HIV
Zurakowski, R
2006 American Control Conference, Vols 1-12, 1-12(): 4800-4805.

AIDS Research and Human Retroviruses
High Frequency of Gross Deletions in 5 ' LTR/gag and nef Genes in Patients Infected with CRF02_AG of HIV Type 1 Who Survived for Over 20 Years: An Association with Korean Red Ginseng
Cho, YK; Jung, YS; Sung, H; Sim, MK; Kim, YK
AIDS Research and Human Retroviruses, 25(5): 535-541.
10.1089/aid.2008.0301
CrossRef
Clinical Infectious Diseases
HIV controllers: A homogeneous group of HIV-1-infected patients with spontaneous control of viral replication
Lambotte, O; Boufassa, F; Madec, Y; Nguyen, A; Goujard, C; Meyer, L; Rouzioux, C; Venet, A; Delfraissy, JF
Clinical Infectious Diseases, 41(7): 1053-1056.

Journal of Virology
Magnitude, breadth, and functional profile of T-cell responses during human immunodeficiency virus primary infection with B and BF viral variants
Turk, G; Gherardi, MM; Laufer, N; Saracoo, M; Luzzi, R; Cox, JH; Cahn, P; Salomon, H
Journal of Virology, 82(6): 2853-2866.
10.1128/JVI.02260-07
CrossRef
Virology
Viral load, organ distribution, histopathological lesions, and cytokine mRNA expression in goats infected with a molecular clone of the caprine arthritis encephalitis virus
Ravazzolo, AP; Nenci, C; Vogt, HR; Waldvogel, A; Obexer-Ruff, G; Peterhans, E; Bertoni, G
Virology, 350(1): 116-127.
10.1016/j.virol.2006.02.014
CrossRef
European Journal of Immunology
Mimotopes selected with antibodies from HIV-1-neutralizing long-term non-progressor plasma
Humbert, M; Antoni, S; Brill, B; Landersz, M; Rodes, B; Soriano, V; Wintergerst, U; Knechten, H; Staszewski, S; von Laer, D; Dittmar, MT; Dietrich, U
European Journal of Immunology, 37(2): 501-515.
10.1002/eji.200636560
CrossRef
Blood
Conservation of unique cell-surface CD antigen mosaics in HIV-1-infected individuals
Woolfson, A; Stebbing, J; Tom, BDM; Stoner, KJ; Gilks, WR; Kreil, DP; Mulligan, SP; Belov, L; Chrisp, JS; Errington, W; Wildfire, A; Erber, WN; Bower, M; Gazzard, B; Christopherson, RI; Scott, MA
Blood, 106(3): 1003-1007.
10.1182/blood-2004-12-4642
CrossRef
AIDS Reviews
Elite HIV controllers: Myth or reality?
Saksena, NK; Rodes, B; Wang, B; Soriano, V
AIDS Reviews, 9(4): 195-207.

Journal of Virology
Genetic characterization of human immunodeficiency virus type 1 in elite controllers: Lack of gross genetic defects or common amino acid changes
Miura, T; Brockman, MA; Brumme, CJ; Brumme, ZL; Carlson, JM; Pereyra, F; Trocha, A; Addo, MM; Block, BL; Rothchild, AC; Baker, BM; Flynn, T; Schneidewind, A; Li, B; Wang, YE; Heckerman, D; Allen, TM; Walker, BD
Journal of Virology, 82(): 8422-8430.
10.1128/JVI.00535-08
CrossRef
Clinical Infectious Diseases
Long-term nonprogression of HIV infection in children: Evaluation of the ANRS prospective french pediatric cohort
Warszawski, J; Lechenadec, J; Faye, A; Dollfus, C; Firtion, G; Meyer, L; Douard, D; Monpoux, F; Tricoire, J; Benmebarek, Y; Rouzioux, C; Blanche, S
Clinical Infectious Diseases, 45(6): 785-794.
10.1086/521165
CrossRef
Journal of Clinical Immunology
Association of IL-12(+) DC with high CD3(+)CD4(-)DR(+) lymphocyte counts in long-term HIV-infected hemophilia patients with clinically stable disease
Daniel, V; Naujokat, C; Sadeghi, M; Zimmermann, R; Huth-Kuhne, A; Opelz, G
Journal of Clinical Immunology, 28(1): 58-72.
10.1007/s10875-007-9133-8
CrossRef
Experimental and Molecular Pathology
HIV-1 Vpr: Mechanisms of G(2) arrest and apoptosis
Andersen, JL; Le Rouzic, E; Planelles, V
Experimental and Molecular Pathology, 85(1): 2-10.
10.1016/j.yexmp.2008.03.015
CrossRef
European Journal of Clinical Investigation
Modulatory effect of mannose-binding lectin on cytokine responses: possible roles in HIV infection
Heggelund, L; Mollnes, TE; Espevik, T; Muller, F; Kristiansen, KI; Aukrust, P; Froland, SS
European Journal of Clinical Investigation, 35(): 765-770.

Journal of Theoretical Biology
A model predictive control based scheduling method for HIV therapy
Zurakowski, R; Teel, AR
Journal of Theoretical Biology, 238(2): 368-382.
10.1016/j.jtbi.2005.05
CrossRef
Journal of Virology
Nef Alleles from human immunodeficiency virus type 1-infected long-term-nonprogressor hemophiliacs with or without late disease progression are defective in enhancing virus replication and CD4 down-regulation
Crotti, A; Neri, F; Corti, D; Ghezzi, S; Heltai, S; Baur, A; Poli, G; Santagostino, E; Vicenzi, E
Journal of Virology, 80(): 10663-10674.
10.1128/JVI.02621-05
CrossRef
AIDS Research and Human Retroviruses
High frequency of gross deletions in the 5 ' LTR and gag regions in HIV type 1-infected long-term survivors treated with Korean red ginseng
Cho, YK; Jung, YS
AIDS Research and Human Retroviruses, 24(2): 181-193.
10.1089/aid.2007.0143
CrossRef
Current Hiv Research
High frequency of grossly deleted nef genes in HIV-1 infected long-term slow progressors treated with Korean red ginseng
Cho, YK; Lim, JY; Jung, YS; Oh, SK; Lee, HJ; Sung, HS
Current Hiv Research, 4(4): 447-457.

Journal of Neurovirology
Impact of human immunodeficiency virus (HIV) subtypes on HIV associated neurological disease
Liner, KJ; Hall, CD; Robertson, KR
Journal of Neurovirology, 13(4): 291-304.
10.1080/13550280701422383
CrossRef
Journal of Infectious Diseases
Clinical Outcomes of Elite Controllers, Viremic Controllers, and Long-Term Nonprogressors in the US Department of Defense HIV Natural History Study
Okulicz, JF; Marconi, VC; Landrum, ML; Wegner, S; Weintrob, A; Ganesan, A; Hale, B; Crum-Cianflone, N; Delmar, J; Barthel, V; Quinnan, G; Agan, BK; Dolan, MJ
Journal of Infectious Diseases, 200(): 1714-1723.
10.1086/646609
CrossRef
AIDS Research and Human Retroviruses
Genetic and biological characterization of recombinant HIV type 1 with Env derived from long-term nonprogressor (LTNP) viruses
Antoni, S; Walz, N; Landersz, M; Humbert, M; Seidl, C; Dittmar, MT; Dietrich, U
AIDS Research and Human Retroviruses, 23(): 1377-1386.
10.1089/aid.2007.0113
CrossRef
Cell Cycle
The role of Vpr in HIV-1 disease progression is independent of its G(2) arrest induction function
Lai, MY; Chen, JJ
Cell Cycle, 5(): 2275-2280.

Journal of Virology
HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control
Emu, B; Sinclair, E; Hatano, H; Ferre, A; Shacklett, B; Martin, JN; McCune, JM; Decks, SG
Journal of Virology, 82(): 5398-5407.
10.1128/JVI.02176-07
CrossRef
Vaccine
Use of predictive markers of HIV disease progression in vaccine trials
Gurunathan, S; El Habib, R; Baglyos, L; Meric, C; Plotkin, S; Dodet, B; Corey, L; Tartaglia, J
Vaccine, 27(): 1997-2015.
10.1016/j.vaccine.2009.01.039
CrossRef
AIDS Research and Human Retroviruses
Viral Genetic Determinants of Nonprogressive HIV Type 1 Subtype C Infection in Antiretroviral Drug-Naive Children
Tzitzivacos, DB; Tiemessen, CT; Stevens, WS; Papathanasopoulos, MA
AIDS Research and Human Retroviruses, 25(): 1141-1148.
10.1089/aid.2009.0080
CrossRef
Experimental Biology and Medicine
The HIV-1 Tat protein selectively enhances CXCR4 and inhibits CCR5 expression in megakaryocytic K562 cells
Mondal, D; Williams, CA; Ali, M; Eilers, M; Agrawal, KC
Experimental Biology and Medicine, 230(9): 631-644.

Journal of Virology
Meta-Analysis To Test the Association of HIV-1 nef Amino Acid Differences and Deletions with Disease Progression
Pushker, R; Jacque, JM; Shields, DC
Journal of Virology, 84(7): 3644-3653.
10.1128/JVI.01959-09
CrossRef
Journal of Immunology
Differential NKp30 inducibility in chimpanzee NK cells and conserved NK cell phenotype and function in long-term HIV-1-infected animals
Rutjens, E; Mazza, S; Biassoni, R; Koopman, G; Radic, L; Fogli, M; Costa, P; Mingari, MC; Moretta, L; Heeney, J; De Maria, A
Journal of Immunology, 178(3): 1702-1712.

Journal of Medical Virology
Immune Activation and Antibody Responses in Non-Progressing Elite Controller Individuals Infected With HIV-1
Bello, G; Velasco-de-Castro, CA; Bongertz, V; Rodrigues, CAS; Giacoia-Gripp, CBW; Pilotto, JH; Grinsztejn, B; Veloso, VG; Morgado, MG
Journal of Medical Virology, 81(): 1681-1690.
10.1002/jmv.21565
CrossRef
AIDS Research and Human Retroviruses
Polymorphisms in Nef associated with different clinical outcomes in HIV type 1 subtype C-infected children
Walker, PR; Ketunuti, M; Choge, IA; Meyers, T; Gray, G; Holmes, EC; Morris, L
AIDS Research and Human Retroviruses, 23(2): 204-215.
10.1089/aid.2006.0080
CrossRef
Blood
Slow disease progression and robust therapy-mediated CD4(+) T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection
Dion, ML; Bordi, R; Zeidan, J; Asaad, R; Boulassel, MR; Routy, JP; Lederman, MM; Sekaly, RP; Cheynier, R
Blood, 109(7): 2912-2920.
10.1182/blood-2006-09-047308
CrossRef
Viral Immunology
AIDS: Is there an answer to the global pandemic? The immune system in HIV infection and control
Maplanka, C
Viral Immunology, 20(3): 331-341.
10.1089/vim.2007.0044
CrossRef
Pathologie Biologie
HIV controllers: a homogeneous group of HIV-1 infected patients with a spontaneous control of viral replication
Lambotte, O; Delfraissy, JF
Pathologie Biologie, 54(): 566-571.
10.1016/j.patbio.2006.07.035
CrossRef
AIDS Research and Human Retroviruses
Full-length characterization of A1/D intersubtype recombinant Genomes from a therapy-induced HIV type 1 controller during acute infection and his noncontrolling partner
Fomsgaard, A; Vinner, L; Therrien, D; Jorgensen, LB; Nielsen, C; Mathiesen, L; Pedersen, C; Corbet, S
AIDS Research and Human Retroviruses, 24(3): 463-472.
10.1089/aid.2006.0294
CrossRef
Current Hiv Research
The presence of antibodies recognizing a peptide derived from the second conserved region of HIV-1 gp120 correlates with non-progressive HIV infection
Djordjevic, A; Veljkovic, M; Antoni, S; Sakarellos-Daitsiotis, M; Krikorian, D; Zevgiti, S; Dietrich, U; Veljkovic, N; Branch, DR
Current Hiv Research, 5(5): 443-448.

Retrovirology
Nef does not contribute to replication differences between R5 pre-AIDS and AIDS HIV-1 clones from patient ACH142
Olivieri, KC; Scoggins, RM; Broderick, B; Powell, MLC; Alexander, MA; Hammarskjold, ML; Rekosh, D; Camerini, D
Retrovirology, 5(): -.
ARTN 42
CrossRef
AIDS Research and Human Retroviruses
Vpr in plasma of HIV type 1-positive patients is correlated with the HIV type 1 RNA titers
Hoshino, S; Sun, B; Konishi, M; Shimura, M; Segawa, T; Hagiwara, Y; Koyanagi, Y; Iwamoto, A; Mimaya, JI; Terunuma, H; Kano, S; Ishizaka, Y
AIDS Research and Human Retroviruses, 23(3): 391-397.
10.1089/aid.2006.0124
CrossRef
Journal of Mathematical Analysis and Applications
The effects of immunity and resistance on the development of AIDS
Abell, M; Braselton, J; Braselton, L
Journal of Mathematical Analysis and Applications, 333(1): 8-23.
10.1016/j.jmaa.2006.12.021
CrossRef
Immunity
Human immunodeficiency virus controllers: Mechanisms of durable virus control in the absence of antiretroviral therapy
Deeks, SG; Walker, BD
Immunity, 27(3): 406-416.
10.1016/j.immuni.2007.08.010
CrossRef
International Journal of Std & AIDS
A very particular case of long-term non-progressor: nineteen consecutive years of follow-up in the absence of any detectable HIV-1 viraemia
Manfredi, R; Sabbatani, S; Fulgaro, C; Fasulo, G
International Journal of Std & AIDS, 19(): 784-785.
10.1258/ijsa.2008.008115
CrossRef
AIDS Research and Human Retroviruses
Genetic and Functional Analysis of HIV Type 1 nef Gene Derived from Long-Term Nonprogressor Children: Association of Attenuated Variants with Slow Progression to Pediatric AIDS
Corro, G; Rocco, CA; De Candia, C; Catano, G; Turk, G; Mangano, A; Aulicino, PC; Bologna, R; Sen, L
AIDS Research and Human Retroviruses, 28(): 1617-1626.
10.1089/aid.2012.0020
CrossRef
AIDS
Vpr and HIV-1 disease progression: R77Q mutation is associated with long-term control of HIV-1 infection in different groups of patients
Mologni, D; Citterio, P; Menzaghi, B; Poma, BZ; Riva, C; Broggini, V; Sinicco, A; Milazzo, L; Adorni, F; Rusconi, S; Galli, M; Riva, A; for the rHoPeS Group,
AIDS, 20(4): 567-574.
10.1097/01.aids.0000210611.60459.0e
PDF (381) | CrossRef
AIDS
Disease progression in macaques with low SIV replication levels: on the relevance of TREC counts
Fang, RH; Khatissian, E; Monceaux, V; Cumont, M; Beq, S; Ameisen, J; Aubertin, A; Israël, N; Estaquier, J; Hurtrel, B
AIDS, 19(7): 663-673.
10.1097/01.aids.0000166089.93574.5a
PDF (1836) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Early Control of HIV-1 Infection in Long-Term Nonprogressors Followed Since Diagnosis in the ANRS SEROCO/HEMOCO Cohort
Madec, Y; Boufassa, F; Avettand-Fenoel, V; Hendou, S; Melard, A; Boucherit, S; Surzyn, J; Meyer, L; Rouzioux, C; for the ANRS SEROCO/HEMOCO Study Group,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 50(1): 19-26.
10.1097/QAI.0b013e31818ce709
PDF (253) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Dual Nucleoside Reverse Transcriptase Inhibitor Therapy in the Combination Antiretroviral Therapy Era and Predictors of Discontinuation or Switch to Combination Antiretroviral Therapy
Selinger-Leneman, H; Matheron, S; Mahamat, A; Moreau, J; Costagliola, D; Abgrall, S; for the Clinical Epidemiology Group of the French Hospital Database on HIV (ANRS CO4),
JAIDS Journal of Acquired Immune Deficiency Syndromes, 47(2): 206-211.
10.1097/QAI.0b013e31815aca91
PDF (88) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors
Sajadi, MM; Constantine, NT; Mann, DL; Charurat, M; Dadzan, E; Kadlecik, P; Redfield, RR
JAIDS Journal of Acquired Immune Deficiency Syndromes, 50(4): 403-408.
10.1097/QAI.0b013e3181945f1e
PDF (158) | CrossRef
The Pediatric Infectious Disease Journal
Virologic and Host Characteristics of Human Immunodeficiency Virus Type 1-Infected Pediatric Long Term Survivors
Alexander, L; Cuchura, L; Simpson, BJ; Andiman, WA
The Pediatric Infectious Disease Journal, 25(2): 135-141.
10.1097/01.inf.0000199299.00345.83
PDF (489) | CrossRef
Back to Top | Article Outline
Keywords:

long-term non-progressors; disease progression; natural history; viral fitness

© 2004 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.