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|Year : 2014 | Volume
| Issue : 1 | Page : 77--78
Commentary : Slow or long-term non-progressor HIV patients: Indian scenario
Division of Clinical Microbiology and Molecular Medicine, All India Institute of Medical Sciences, New Delhi, India
Division of Clinical Microbiology and Molecular Medicine, All India Institute of Medical Sciences, New Delhi
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Singh S. Commentary : Slow or long-term non-progressor HIV patients: Indian scenario
.Indian J Med Microbiol 2014;32:77-78
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Singh S. Commentary : Slow or long-term non-progressor HIV patients: Indian scenario
. Indian J Med Microbiol [serial online] 2014 [cited 2020 Feb 18 ];32:77-78
Available from: http://www.ijmm.org/text.asp?2014/32/1/77/124327
After acquired immunodeficiency syndrome (AIDS) epidemic in 1981 researchers realised that about 2-5% human immunodeficiency virus (HIV)-1 positive patients did not develop AIDS manifestations for several years nor had a markedly slow disease progression to AIDS. These persons are referred as HIV-1 long-term non-progressors (LTNPs) or long-term slow progressors (LTSPs), respectively. 
HIV reached India in 1986 and since then India has remained a high burden country with approximately 2.1 million HIV-1 positives in 2013.  But data on proportion of LTNP and LTSP in Indian HIV-1 infected persons are scarce. Recently Radhakrishna et al., published a small study of 26 paediatric cases. Their follow-up period was for 10-15 years. These children remained asymptomatic for 15 years, but after that 18 of these children developed AIDS and finally only 6 remained as LTNPs. The CD4 + count ranged from 17 to 2214 cells/μl with mean count of 586 ± 162 cells/μl of LTNPs and 661 ± 276 cells/μl for LTSPs. There was no significant difference in any other biochemical and haematological parameters between the two groups except for serum albumin (P < 0.05).
Various definitions of LTNP and LTSP have been reported at different time periods, mainly because of better tools of diagnosis and monitoring came into existence in the past 20 years. According to the recent definition, LTNP is one who shows low detectable plasma viraemia (<5000 HIV-RNA copies/ml). But there is another group of persons under this definition who show plasma HIV-RNA values persistently below 50 copies/ml, and these persons are termed 'elite' or 'natural controllers'.  By early 90s, basic biology of HIV transmission and replication was well studied and it was established that entry of HIV-1 into human host target cell requires CD4 + cell receptors and a specific β-chemokine co-receptors-5 (CCR5). It was reported that without these receptors and co-receptors, the virus cannot attach and invade the target cells. A 32 base pair deletion mutation (Δ32) in the second extracellular loop encoding region of this CCR5 gene was strongly associated with relative resistance to HIV-1 and slower progression to AIDS. The Δ 32/Δ32 homozygotes were reported to resist the HIV-1 infection despite the repeated exposure while CCR5/Δ32 heterozygotes had slow progression to AIDS. Among Caucasians, frequency of CCR5/Δ32 heterozygotes and Δ32/Δ32 homozygotes was reported between 16-35% and 1.0-3.6%, respectively.  However, from India CCR5/Δ32 heterozygocity was reported only in 1 out of 100 healthy persons studied. 
In recent years several other host factors are identified. These include polymorphisms in SDF-1-3'A and CCR2-64I and heterozygosity at HLA class-I loci (HLA-A, HLA-B and HLA-C). , It is reported that HLA-B*81:01 and B * 39:10 alleles are associated with viraemic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and CTL mediated escape mutations in this epitope. It has been predicted that HLA-B*27 and HLA-B*57 exert a protective effect on disease progression to AIDS in HIV-1 infected individuals.
In this issue of IJMM, Dr Sehgal et al ., report a male patient who was first detected as HIV positive in 1993. They discuss patient's follow-up account of the past 20 years, which is probably the longest follow-up period.  The case is interesting because he was married for 15 years and the couple had two children but wife remained HIV negative till this report is published. The patient was negative for both HLA B27 and B57 antigens and his CD4 + lymphocytes showed normal CCR5 and CxCR4 expression as measured by flowcytometry and no cytokine profile shift was demonstrated.
There are two important observations in this case report. First is slow progression and the second is discordant couple. As far as the slow progression of HIV-1 disease is concerned, authors must have excluded the possibility of taking any traditional or herbal medicines during the asymptomatic phase. The authors have also not discussed the social background of the patient. As we know that in early years of HIV epidemic, when HAART was not freely available in India, stigma and frustration in HIV positive patients was extremely high and more than 90% of rural patients sought herbal or Ayurvedic medications. Though traditional healers have been claiming HIV cure but this claim was never proved. Nevertheless it is true that several herbal medicines have immunomodulatory effect and these patents remained asymptomatic and maintained high CD4 + lymphocyte counts for several years, despite significant viral load.
To verify such claims we carried out a small study  in 1997-1998, in which 37 recently diagnosed HIV-1 seropositive patients were administered directly supervised poly herbal combination known as Immu-21 (R) . All patients were detected HIV-1 infected between year 1992 and 1996. Of the 37 patients on Ayurvedic medicine, 25 were males and 12 females. The mean age was 31.89 ± 11.1 years. The mean age of control group who opted for anti-retroviral therapy was 33.5 ± 9.2 years. The herbal capsules were given twice daily for 2 years and patients followed up for 5 years after stopping the medicines. During the treatment period, six patients (16.2%) died and seven (19.0%) lost the follow- up after 6 months and another six after 12 months of medication. Thus, 18 patients successfully completed the 2 years drug trial. In the control group, three (10%) patients died but nine (30%) patients were lost for follow-up. In study group the average basal CD4 + cell count was 331.6/ml, which declined at the rate of 6.5/μl/month and reached 311.9/μl after first 3 months. After first 3 months, the decline stopped and at the end of 6 months of treatment the mean CD4 + cell count rose to 407.6/μl. After one year CD4 + cell count was 473.4/μl. However, no viricidal effect was observed.  In cases of anti-retroviral treatment group, the rise in CD4 + cell count was less significant but sharp. The mean CD4 + cell count increase was from 110/μl CD4 + to 320/μl. Six of the 18 patients on herbal medication remained asymptomatic till 2010 when they developed symptoms and were put on HAART. One female patient is still asymptomatic and on no medication, till this date. Hence it can be concluded that several host and nutritional factors contribute to the slow progression.
Another observation is the discordant couple having children. In this context it is very important to mention that it does not matter how professional counselling is provided still some patients will give false information very convincingly. We also had one interesting case similar to this. A female patient was tested HIV-1 positive in 1995 when her second baby was born with multiple congenital abnormalities. The baby died within 18 months of birth. Earlier, before this delivery, she was transfused two units of blood for post-partum haemorrhage in 1992. In 1997 she again delivered two daughters out of which one was given to relatives immediately after birth while the other one was weaned by the biological mother. Two years later the daughter weaned by the mother was also tested HIV-1 positive. Her husband was repeatedly tested HIV negative till 2006. They both revealed during counselling that their marital relations were normal and they had both protected as well as unprotected sex. We performed genetic studies on her husband that included SDF-1α (stromal cell-derived factor 1-alpha) and CCR5/Δ32 polymerase chain reaction (PCR) assays, but no mutation was identified. Interestingly in 2006, her husband filed a divorce petition alleging her for infidelity, mentioning that they are not having any marital relations since 1995 and two daughters born to her are not from him.
Though from this illustration we cannot make any strong statement but such situations should also be kept in mind, which might misdirect the approach of laboratory investigations.
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