Correspondence
Long-Term Survivors of Human Immunodeficiency Virus Type 1 Infection
N Engl J Med 1995; 332:1646-1648June 15, 1995
- Article
To the Editor:
The recent papers by Cao et al.1 and Pantaleo et al.2 (Jan. 26 issue) focus on characteristics of long-term survivors of human immunodeficiency virus type 1 (HIV-1) infection. The authors quantitated HIV-1 in plasma with a modification of the branched-DNA signal-amplification assay and a competitive reverse transcriptase–polymerase-chain-reaction (PCR) assay, respectively.
We evaluated changes over a 12-month period in the viral load in the plasma of 11 patients who fulfilled the same criteria for long-term survivors of HIV-1 infection that were used by Cao et al.1 The 11 patients were documented to have been seropositive for HIV-1 (with confirmation by the Western blot assay) for at least 10 years. Plasma samples obtained since 1993 and stored at -70°C were available for all patients. We determined the viral load (the number of copies of RNA per milliliter) in samples obtained 12 months apart, using a reverse transcriptase–PCR assay (Roche Molecular Systems), as previously described.3 We also evaluated CD4 cells as both mean counts and percentages of the total number of lymphocytes. The presence of MT-2 tropism or of mutation in HIV-1 reverse transcriptase at codon 215 was also determined as previously described.4,5 The relevant results are shown in Table 1Table 1
Clinical Characteristics of 11 Long-Term Survivors of HIV-1 Infection..In six patients there was a slight increase in the mean viral load after 12 months (from 8996 to 20,074 copies per milliliter), whereas in the remaining five this value did not change significantly (declining from 5514 to 3875 copies per milliliter). In evaluating long-term survivors, techniques for detecting very low viral loads accurately should be used, such as the reverse transcriptase–PCR assay, which detects levels greater than 200 copies per milliliter. Because of the variability of results with this technique, we think that only variation greater than 1/2 log10 should be considered significant.
Longer follow-up in patients with long-term HIV-1 infection should be capable of indicating whether the increases in the viral load in some patients are progressive and will lead to clinical progression. We believe that periodic evaluation of the viral load will be useful in all such patients.
5 ReferencesB. Clotet, M.D.
L. Ruiz, M.D.
A. Ibañez, M.D.
Hospital Universitari Germans Trias i Pujol, 08916 Barcelona, Spain1
Cao Y ,Qin L ,Zhang L ,Safrit J ,Ho DD . Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
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Pantaleo G ,Menzo S ,Vaccarezza M , et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
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Mulder J ,McKinney N ,Christopherson C ,Sninsky J ,Greenfield L ,Kwok S . Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 1994;32:292-300
Web of Science | Medline4
Lacey SF ,Larder BA . Mutagenic study of codons 74 and 215 of the human immunodeficiency virus type 1 reverse transcriptase, which are significant in nucleoside analog resistance. J Virol 1994;68:3421-3424
Web of Science | Medline5
Koot M ,Vos AH ,Keet RP , et al. HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay. AIDS 1992;6:49-54
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To the Editor:
The articles by Cao et al.,1 Pantaleo et al.,2 and Kirchhoff et al.3 make it clear that long-term survival with HIV infection but without clinical progression is possible. As Baltimore points out in his editorial,4 however, with one exception3 the findings in subjects with nonprogressive infection could be the consequence of nonprogression rather than the cause. That is, the findings of more “benign” patterns of immune function and viral expression in patients with nonprogressive infection are similar to the findings in early infection that has yet to progress.
In the two comparative studies, patients without progression of their infections are compared implicitly1 or explicitly2 with patients whose infections had progressed. However, it seems to me that one way to disentangle the cause-and-effect relation in nonprogressive disease is to compare patients without progression with patients whose disease has not yet progressed. That is, one might select as the comparison sample recently infected patients who are matched with the long-term survivors according to the numbers and function of T-cell subgroups, immune reactivity, and the like. Then a comparison of the groups indicating differences in viral burden, antibody levels, and viral protein sequences could be interpreted more directly as showing nonprogressive rather than “preprogressive” infection in the long-term survivors.
Admittedly, the “preprogressive” group would contain some patients who might eventually be classified as having nonprogressive infection. However, since the proportion of such patients is likely to be very small, clinically relevant differences would certainly still be apparent.
4 ReferencesJohn Whyte, M.D., Ph.D
Moss Rehabilitation Research Institute, Philadelphia, PA 19141-30991
Cao Y ,Qin L ,Zhang L ,Safrit J ,Ho DD . Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
Full Text | Web of Science | Medline2
Pantaleo G ,Menzo S ,Vaccarezza M , et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
Full Text | Web of Science | Medline3
Kirchhoff F ,Greenough TC ,Brettler DB ,Sullivan JL ,Desrosiers RC . Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 1995;332:228-232
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Baltimore D . Lessons from people with nonprogressive HIV infection. N Engl J Med 1995;332:259-260
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To the Editor:
In the reports of the virologic, immunologic, histologic, cytologic, and genetic characteristics of persons with long-term nonprogressive HIV infection,1-3 the differences in the case definitions used call into question whether investigators were investigating precisely the same phenomenon.
Of particular interest is Subject 7 in the study by Cao et al.,1 a woman who is reported to have delivered an HIV-infected infant 13 years before the time of these studies. This patient was also one of four from whom virus was cultured and one of two whose virus was determined to be attenuated on the basis of growth characteristics. Because this patient's infant was presumably infected with the same strain of HIV, it would be interesting, and perhaps crucially relevant, to know the clinical course of the baby. Might this child represent a study in perinatal immunization? Is information about the child available?
3 ReferencesLisa M. Dunkle, M.D.
Bristol-Myers Squibb, Wallingford, CT 06492-76601
Cao Y ,Qin L ,Zhang L ,Safrit J ,Ho DD . Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
Full Text | Web of Science | Medline2
Pantaleo G ,Menzo S ,Vaccarezza M , et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
Full Text | Web of Science | Medline3
Kirchhoff F ,Greenough TC ,Brettler DB ,Sullivan JL ,Desrosiers RC . Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med 1995;332:228-232
Full Text | Web of Science | Medline
To the Editor:
Scrutiny of the data provided by Cao et al. and Pantaleo et al. suggests that the genetic characteristics of long-term survivors of HIV-1 infection contribute to their low infectivity and to the virus-specific immune responses. HLA-DR11 and DR15 and probably DQ1 and DQ3 are overrepresented among the long-term survivors, as compared with a healthy white population. A variety of HLA alleles have been associated with susceptibility to AIDS in HIV-positive subjects with disease progression, and with AIDS-related manifestations.1-4 It is interesting that DR5 and DR2, of which DR11 and DR15 are respective subcategories, have been associated with AIDS-related Kaposi's sarcoma,1,2 which suggests that whereas these antigens provide resistance to HIV-1 infectivity, they perhaps confer susceptibility to another virus specific for Kaposi's sarcoma.5
Our knowledge of resistance to HIV-1 and of the long-term survival of infected subjects would be advanced by a detailed study of their HLA alleles, using molecular techniques that compare the results in the long-term survivors with those in patients with the more usual course of the disease.
5 ReferencesNadir R. Farid, M.B., B.S.
3639 St. Mary's Place, NW, Washington, DC 200071
Freidman-Kien AE ,Laubenstein JL ,Rubinstein P , et al. Disseminated Kaposi's sarcoma in homosexual men. Ann Intern Med 1982;96:693-700
Web of Science | Medline2
Pollack MS ,Safai B ,Dupont B . HLA-DR5 and DR2 are susceptibility factors for acquired immunodeficiency syndrome with Kaposi's sarcoma in different ethnic subpopulations. Dis Markers 1983;1:135-1393
Kaplan C ,Muller JY ,Doinel C , et al. HLA-associated susceptibility to acquired immune deficiency syndrome in HIV-1-seropositive subjects. Hum Hered 1990;40:290-298
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Steel CM ,Ludlam CA ,Beatson D , et al. HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease. Lancet 1988;1:1185-1188
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Chang Y ,Cesarman E ,Pessin MS , et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869
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Author/Editor Response
The authors reply:
To the Editor: The observations of Clotet et al. are appreciated. Among our long-term survivors, no substantial change in viral load has been observed over a period of one to eight years.
Dr. Whyte rightly points out that the virologic and immunologic profiles of long-term survivors may resemble those of patients early after seroconversion. However, a part of his proposed study has already been conducted by Saksela et al.,1 who showed that the extent of HIV-1 expression in peripheral-blood mononuclear cells in vivo precedes (and is predictive of) the decline in the CD4 lymphocyte count and the progression of disease.
Dr. Dunkle requests additional information on the child of our Subject 7. A normal female child was born to this subject in August 1982. HIV-1 infection was diagnosed in the mid-1980s, and the child remained well, with a normal CD4 lymphocyte count, until 1990, when a progressive decline in CD4 cell counts was observed despite the use of antiretroviral agents. The child died of complications of Pneumocystis carinii pneumonia in May 1993. Thus, the overall course of the child's disease may be considered protracted for a case of perinatal HIV-1 infection. As we stated in our paper, an HIV-1 isolate with attenuated growth properties was obtained from Subject 7. We have yet to study samples obtained from the child, but it is possible that the attenuated HIV-1 from the mother evolved into a more virulent form in the child. Alternatively, a relatively attenuated virus may be more virulent in a newborn or young child, as has been observed with a defective simian immunodeficiency virus in newborn macaques.2
From the published results, Dr. Farid suggests that specific HLA types may be associated with nonprogression. Although this suggestion may be correct, no definitive conclusion can be drawn on the basis of the limited data published in our article. Large epidemiologic studies are required.
We wish to provide follow-up data on Subject 9. Dr. Cladd Stevens of the New York Blood Center recently informed us that this subject's disease progressed to AIDS in the period after our analysis. This development, though disturbing, is informative, since we were concerned that this subject, unlike Subjects 1 through 8, “had higher viral burdens and wild-type–like viruses”; in our article, we stated that “it is not clear that [Subjects 9 and 10] . . . will not have progressive disease in the coming years.”3
3 ReferencesDavid D. Ho, M.D.
Yunzhen Cao, M.D.
Aaron Diamond AIDS Research Center, New York, NY 100161
Saksela K ,Stevens C ,Rubinstein P ,Baltimore D . Human immunodeficiency virus type 1 mRNA expression in peripheral blood cells predicts disease progression independently of the numbers of CD4+ lymphocytes. Proc Natl Acad Sci U S A 1994;91:1104-1108
CrossRef | Web of Science | Medline2
Baba TW ,Jeong YS ,Penninck D , et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 1995;267:1820-1825
CrossRef | Web of Science | Medline3
Cao Y ,Qin L ,Zhang L ,Safrit J ,Ho DD . Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
Full Text | Web of Science | Medline
Author/Editor Response
Clotet et al. have made a series of virologic and immunologic measurements in a group of 11 patients with nonprogressive HIV infection. In particular, they have evaluated viremia with a competitive reverse transcription–PCR assay. No significant changes in the levels of viremia were observed during a 12-month period. The relative stability of viremia over time in persons with nonprogressive disease is consistent with the findings of our study,1 in which viremia remained relatively unchanged over a five-year period in a similar group of HIV-infected persons. In this regard, it is likely that the group will be heterogeneous, with viremia remaining stable for long periods in some and increasing or decreasing with time in others. It would obviously be interesting and important to correlate changes or lack of changes in viremia over time with the ultimate clinical course.
Dr. Whyte suggests that it would be interesting to compare the virologic and immunologic measures in HIV-infected persons who have nonprogressive disease with those in persons with early-stage HIV disease who have CD4+ T-cell counts comparable to those of persons with long-term nonprogressive HIV infection. We totally agree, and in fact we are currently comparing the virologic and immunologic measures in persons who have recently seroconverted and whose CD4+ T-cell counts are above 600 per cubic millimeter with those in persons with nonprogressive infection.
Dr. Farid raises the possibility that genetic characteristics associated with certain HLA haplotypes may have an important role in the lack of progression of disease in some HIV-infected persons. We certainly agree, but because of the limited number of persons in our study1 and in the study by Cao et al.,2 it is virtually impossible to determine the statistical significance of the HLA haplotypes in the persons with long-term nonprogressive HIV infection. However, this issue is currently being examined in a large number of such persons by the Multicenter AIDS Cohort Study and the San Francisco City Clinic Cohort investigators.
2 ReferencesGiuseppe Pantaleo, M.D.
Anthony S. Fauci, M.D.
National Institutes of Health, Bethesda, MD 20892-25201
Pantaleo G ,Menzo S ,Vaccarezza M , et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
Full Text | Web of Science | Medline2
Cao Y ,Qin L ,Zhang L ,Safrit J ,Ho DD . Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
Full Text | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
J Durant, P Dellamonica. (1995) Les traitements immunomodulateurs au cours de l'infection à VIH: bases rationnelles et perspectives thérapeutiques. La Revue de Médecine Interne 16, 308s-312s
CrossRef
