Mutations in HIV proteins do indeed sometimes alter function. 8 November 2003
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Brian T Foley,
HIV Researcher
Los Alamos national Lab, Los Alamos, NM 87545 USA

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Re: Mutations in HIV proteins do indeed sometimes alter function.

The Perth group wrote:
As far as the effect of protein variability on their function is concerned, let us quote from a recent article published in Nature: “Small genetic variations between people — or polymorphisms — can alter the behaviour of proteins that carry a drug to its target cells or tissues, cripple the enzymes that activate a drug or aid its removal from the body, or alter the structure of the receptor to which a drug is supposed to bind. Variation in immune-system genes can also influence how particular drugs are tolerated. Together, these subtle genetic variations mean that the dose at which a drug will work may vary hugely from person to person. And with today's 'one-size-fits-all' prescribing, that can lead to life-threatening adverse reactions or to a drug completely failing to do its job. Yet the genomics revolution has given us the tools to identify people who don't fit the standard prescribing mould. Single nucleotide polymorphisms, or SNPs, are single-letter changes in the genetic code that are scattered throughout the genome. They can now be profiled with increasing efficiency, and used to highlight polymorphic genes that influence our response to individual drugs.” (1)
(1) (2003) Nature 425:760-762.

That paper states that single nucleotide polymorphisms “CAN” result in one or more of these effects. It does not state that every single nucleotide change DOES result in a functional change. It is true that some single base changes in DNA result in a change in the amino acid encoded by a gene, these are called nonsynonymous mutations. It has been well established that some nonsynonymous mutations in HIV-1 M group subtype B viruses are highly selected by antiretroviral monotherapy. For one example, monotherapy with zidovudine (AZT) rapidly proved to be of almost no long-term benefit to patients, despite its obvious short-term benefits, because of this type of drug-resistance mutation.

Here are just a few of the hundreds of papers that have been published on this topic:

1) Boucher CA, O'Sullivan E, Mulder JW, Ramautarsing C, Kellam P, Darby G, Lange JM, Goudsmit J, Larder BA.
Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects.
J Infect Dis. 1992 Jan;165(1):105-10.
PMID: 1370174

2) Larder BA, Kemp SD.
Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT).
Science. 1989 Dec 1;246(4934):1155-8.
PMID: 2479983

3) Larder BA, Kellam P, Kemp SD.
Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes.
AIDS. 1991 Feb;5(2):137-44.
PMID: 1709563

4) Richman DD. Related
Emergence of mutant HIV reverse transcriptase conferring resistance to AZT.
J Enzyme Inhib. 1992;6(1):55-64.
PMID: 1285303

Resistance mutations which provide resistance to other nucleoside analogs have been characterized, as have mutations which provide resistance to protease inhibitors. An equal or greater problem is the selection of mutations which provide for escape from immunological control of the virus. Here are a few of the hundreds of papers on that topic:

1) Kohler H, Goudsmit J, Nara P. Related
Clonal dominance: cause for a limited and failing immune response to HIV-1 infection and vaccination.
J Acquir Immune Defic Syndr. 1992;5(11):1158-68.
PMID: 1403647

2) Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, Komarova NL, Nowak MA, Hahn BH, Kwong PD, Shaw GM.
Antibody neutralization and escape by HIV-1.
Nature. 2003 Mar 20;422(6929):307-12.
PMID: 12646921

3) Peterlin BM, Trono D.
Hide, shield and strike back: how HIV-infected cells avoid immune eradication.
Nat Rev Immunol. 2003 Feb;3(2):97-107.
PMID: 12563294

4) : Lue J, Hsu M, Yang D, Marx P, Chen Z, Cheng-Mayer C.
Addition of a single gp120 glycan confers increased binding to dendritic cell-specific ICAM-3-grabbing nonintegrin and neutralization escape to human immunodeficiency virus type 1.
J Virol. 2002 Oct;76(20):10299-306.
PMID: 12239306

The Perth group wrote:
Would Christopher Noble please tell us:

(i) Where is the proof that “HIV” strains have diverged over time?

Here are a few of the hundreds of papers on that topic:

1) Robbins KE, Lemey P, Pybus OG, Jaffe HW, Youngpairoj AS, Brown TM, Salemi M, Vandamme AM, Kalish ML.
U.S. Human immunodeficiency virus type 1 epidemic: date of origin, population history, and characterization of early strains.
J Virol. 2003 Jun;77(11):6359-66.
PMID: 12743293

2) Biggar RJ, Janes M, Pilon R, Roy R, Broadhead R, Kumwenda N, Taha TE, Cassol S.
Human immunodeficiency virus type 1 infection in twin pairs infected at birth.
J Infect Dis. 2002 Jul 15;186(2):281-5. Epub 2002 Jun 17.
PMID: 12134267

3) Loemba H, Brenner B, Parniak MA, Ma'ayan S, Spira B, Moisi D, Oliveira M, Detorio M, Wainberg MA.
Genetic divergence of human immunodeficiency virus type 1 Ethiopian clade C reverse transcriptase (RT) and rapid development of resistance against nonnucleoside inhibitors of RT.
Antimicrob Agents Chemother. 2002 Jul;46(7):2087-94.
PMID: 12069959

4) Nowak P, Karlsson AC, Naver L, Bohlin AB, Piasek A, Sonnerborg A.
The selection and evolution of viral quasispecies in HIV-1 infected children.
HIV Med. 2002 Jan;3(1):1-11.
PMID: 12059945

5) Casado C, Garcia S, Rodriguez C, del Romero J, Bello G, Lopez-Galindez C.
Different evolutionary patterns are found within human immunodeficiency virus type 1-infected patients.
J Gen Virol. 2001 Oct;82(Pt 10):2495-508.
PMID: 11562542

6) Frost SD, Gunthard HF, Wong JK, Havlir D, Richman DD, Leigh Brown AJ.
Evidence for positive selection driving the evolution of HIV-1 env under potent antiviral therapy.
Virology. 2001 Jun 5;284(2):250-8.
PMID: 11384224

7) Foley B, Pan H, Buchbinder S, Delwart EL. Related
Apparent founder effect during the early years of the San Francisco HIV type 1 epidemic (1978-1979).
AIDS Res Hum Retroviruses. 2000 Oct 10;16(15):1463-9.
PMID: 11054259

8) Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, Farzadegan H, Gupta P, Rinaldo CR, Learn GH, He X, Huang XL, Mullins JI.
Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection.
J Virol. 1999 Dec;73(12):10489-502.
PMID: 10559367

9) Courgnaud V, Saurin W, Villinger F, Sonigo P.
Different evolution of simian immunodeficiency virus in a natural host and a new host.
Virology. 1998 Jul 20;247(1):41-50.
PMID: 9683570

10) Wei Q, Fultz PN.
Extensive diversification of human immunodeficiency virus type 1 subtype B strains during dual infection of a chimpanzee that progressed to AIDS.
J Virol. 1998 Apr;72(4):3005-17.
PMID: 9525623

11) Gaschen B, Taylor J, Yusim K, Foley B, Gao F, Lang D, Novitsky V, Haynes B, Hahn BH, Bhattacharya T, Korber B.
Diversity considerations in HIV-1 vaccine selection.
Science. 2002 Jun 28;296(5577):2354-60.
PMID: 12089434

12) Gao F, Trask SA, Hui H, Mamaeva O, Chen Y, Theodore TS, Foley BT, Korber BT, Shaw GM, Hahn BH.
Molecular characterization of a highly divergent HIV type 1 isolate obtained early in the AIDS epidemic from the Democratic Republic of Congo.
AIDS Res Hum Retroviruses. 2001 Aug 10;17(12):1217-22.
PMID: 11522191

13) Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD.
An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.
Nature. 1998 Feb 5;391(6667):594-7.
PMID: 9468138

14) Salemi M, Strimmer K, Hall WW, Duffy M, Delaporte E, Mboup S, Peeters M, Vandamme AM.
Dating the common ancestor of SIVcpz and HIV-1 group M and the origin of HIV-1 subtypes using a new method to uncover clock-like molecular evolution.
FASEB J. 2001 Feb;15(2):276-8. Epub 2000 Dec 08.
PMID: 11156935

15) Korber B, Muldoon M, Theiler J, Gao F, Gupta R, Lapedes A, Hahn BH, Wolinsky S, Bhattacharya T.
Timing the ancestor of the HIV-1 pandemic strains.
Science. 2000 Jun 9;288(5472):1789-96.
PMID: 10846155

16) Leitner T, Kumar S, Albert J.
Tempo and mode of nucleotide substitutions in gag and env gene fragments in human immunodeficiency virus type 1 populations with a known transmission history.
J Virol. 1997 Jun;71(6):4761-70.
PMID: 9151870

17) Leitner T, Albert J.
The molecular clock of HIV-1 unveiled through analysis of a known transmission history.
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10752-7.
PMID: 10485898

18) Blanchard A, Ferris S, Chamaret S, Guetard D, Montagnier L.
Molecular evidence for nosocomial transmission of human immunodeficiency virus from a surgeon to one of his patients.
J Virol. 1998 May;72(5):4537-40.
PMID: 9557756

The Perth group wrote:
As far back as 1989 – 1992 when the “extraordinary variability” of the “HIV” genome was not known, researchers from the Pasteur Institute including Wain-Hobson were of the opinion that: “The task of defining HIV infection in molecular terms will be difficult” (5,6)
(5) Vartanian JP, Meyerhans A, Henry M, Wain-Hobson S. (1992)
High-resolution structure of an HIV-1 quasispecies: identification of novel coding sequences.
AIDS 6(10): 1095-1098.
(6) Meyerhans A, Cheynier R, Albert J, Seth M, Kwok S, Sninsky J, et al. (1989)
Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations.
Cell 58(5): 901-910.

In fact, much was known about the variability and diversity of HIV-1, HIV-2 and several simian immunodeficiency viruses by the 1989-1992 time period. Reference 5 does not mention anything about a difficulty in defining HIV infection. Reference 6 makes that statement in the abstract, when discussing how difficult it is to describe, in molecular terms, the entire repertoire of virions present in at any one time within the viral quasispecies of a single infected host. He was most certainly not saying that it is difficult to determine or define whether or not a given patient is infected.

Here are a few papers which show that the diversity of HIV-1, HIV-2 and a few SIVs were well established by 1992:

1) Ramsay AJ.
Diversity and variation in human immunodeficiency virus: implications for immune control.
Immunol Cell Biol. 1992 Jun;70 ( Pt 3):215-21.
PMID: 1452223

2) Peeters M, Fransen K, Delaporte E, Van den Haesevelde M, Gershy-Damet GM, Kestens L, van der Groen G, Piot P.
Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee.
AIDS. 1992 May;6(5):447-51.
PMID: 1616649

3) Allan JS, Short M, Taylor ME, Su S, Hirsch VM, Johnson PR, Shaw GM, Hahn BH.
Species-specific diversity among simian immunodeficiency viruses from African green monkeys.
J Virol. 1991 Jun;65(6):2816-28.
PMID: 2033656

4) Simmonds P, Balfe P, Ludlam CA, Bishop JO, Brown AJ.
Analysis of sequence diversity in hypervariable regions of the external glycoprotein of human immunodeficiency virus type 1.
J Virol. 1990 Dec;64(12):5840-50.
PMID: 2243378

5) Oram JD, Downing RG, Roff M, Clegg JC, Serwadda D, Carswell JW.
Nucleotide sequence of a Ugandan HIV-1 provirus reveals genetic diversity from other HIV-1 isolates.
AIDS Res Hum Retroviruses. 1990 Sep;6(9):1073-8.
PMID: 2265025

6) Tristem M, Hill F, Karpas A.
Nucleotide sequence of a Guinea-Bissau-derived human immunodeficiency virus type 2 proviral clone (HIV-2CAM2).
J Gen Virol. 1991 Mar;72 ( Pt 3):721-4.
PMID: 2005437

7) Srinivasan A, York D, Butler D Jr, Jannoun-Nasr R, Getchell J, McCormick J, Ou CY, Myers G, Smith T, Chen E, et al.
Molecular characterization of HIV-1 isolated from a serum collected in 1976: nucleotide sequence comparison to recent isolates and generation of hybrid HIV.
AIDS Res Hum Retroviruses. 1989 Apr;5(2):121-9.
PMID: 2713163

8) Hasegawa A, Tsujimoto H, Maki N, Ishikawa K, Miura T, Fukasawa M, Miki K, Hayami M.
Genomic divergence of HIV-2 from Ghana.
AIDS Res Hum Retroviruses. 1989 Dec;5(6):593-604.
PMID: 2611042

And many alternative procedures for the detection of HIV infection in human and simian blood was well established by that time.

1) U.S. Food and Drug Administration.
General biological products standards, additional standards for human blood and blood products; test for antibody to human immunodeficiency virus (HIV); final rule.
Fed Regist. 1988 Jan 5;53(2):111-7.
PMID: 11655883

2) Joyce C, Anderson I
US licenses blood test for AIDS.
New Sci. 1985 Mar 7;105(1446):3-4.
PMID: 11655676

3) Bayer R, Levine C, Wolf SM.
HIV antibody screening. An ethical framework for evaluating proposed programs.
JAMA. 1986 Oct 3;256(13):1768-74.
PMID: 3018307

4) Sivak SL, Wormser GP.
Predictive value of a screening test for antibodies to HTLV-III.
Am J Clin Pathol. 1986 Jun;85(6):700-3.
PMID: 3010700

5) Ellwein LB, Purtilo DT, Purtilo RB.
Decision analysis of the HTLV-III screening test for blood donors.
AIDS Res. 1986 Feb;2(1):5-17.
PMID: 3013219

Competing interests: None declared