Taking multiple infections of cells and recombination into account leads to small within-host effective-population-size estimates of HIV-1.
Whether HIV-1 evolution in infected individuals is dominated by deterministic or stochastic effects remains unclear because current estimates of the effective population size of HIV-1 in vivo, N(e), are widely varying. Models assuming HIV-1 evolution to be neutral estimate N(e)~10²-10⁴, smaller than the inverse mutation rate of HIV-1 (~10⁵), implying the predominance of stochastic forces. In contrast, a model that includes selection estimates N(e)>10⁵, suggesting that deterministic forces would hold sway. The consequent uncertainty in the nature of HIV-1 evolution compromises our ability to describe disease progression and outcomes of therapy. We perform detailed bit-string simulations of viral evolution that consider large genome lengths and incorporate the key evolutionary processes underlying the genomic diversification of HIV-1 in infected individuals, namely, mutation, multiple infections of cells, recombination, selection, and epistatic interactions between multiple loci. Our simulations describe quantitatively the evolution of HIV-1 diversity and divergence in patients. From comparisons of our simulations with patient data, we estimate N(e)~10³-10⁴, implying predominantly stochastic evolution. Interestingly, we find that N(e) and the viral generation time are correlated with the disease progression time, presenting a route to a priori prediction of disease progression in patients. Further, we show that the previous estimate of N(e)>10⁵ reduces as the frequencies of multiple infections of cells and recombination assumed increase. Our simulations with N(e)~10³-10⁴ may be employed to estimate markers of disease progression and outcomes of therapy that depend on the evolution of viral diversity and divergence.
Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.
Rajesh
R
Balagam
Vasantika
V
Singh
Aparna Raju
AR
Sagi
Narendra M
NM
Dixit
D002460:Cell Line; D003198:Computer Simulation; D018450:Disease Progression; D019143:Evolution, Molecular; D016679:Genome, Viral; D015658:HIV Infections / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011995:Recombination, Genetic
Bioessays. 2004 Feb;26(2):180-8
14745836
Nat Rev Genet. 2009 Mar;10(3):195-205
19204717
J Virol. 2010 Oct;84(19):10230-40
20668070
J Med Virol. 2006;78 Suppl 1:S7-S12
16622870
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2187-91
10051616
PLoS Comput Biol. 2009 Mar;5(3):e1000305
19282958
J Gen Virol. 2005 Nov;86(Pt 11):3109-3118
16227234
Mol Biol Evol. 2004 Oct;21(10):1902-12
15215321
Infect Genet Evol. 2007 Jul;7(4):476-83
17369105
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6975-80
11381143
J Mol Evol. 1980 Dec;16(2):111-20
7463489
Virology. 2006 Mar 30;347(1):140-6
16387340
Mol Biol Evol. 2007 Feb;24(2):574-86
17138627
J Virol. 1995 Aug;69(8):5087-94
7541846
Nature. 1995 May 18;375(6528):194-5; author reply 198
7746314
Trends Microbiol. 2006 Dec;14(12):507-11
17049239
Genetics. 2004 Mar;166(3):1155-64
15082537
Mol Biol Evol. 2005 Mar;22(3):456-68
15509726
Genetics. 1931 Mar;16(2):97-159
17246615
Curr Opin HIV AIDS. 2008 Jan;3(1):28-35
19372941
Genetics. 2000 Jun;155(2):909-19
10835409
PLoS Genet. 2009 Mar;5(3):e1000431
19300501
Theor Popul Biol. 1970 May;1(1):88-100
5527627
J Gen Virol. 2008 Jun;89(Pt 6):1467-1477
18474563
J Virol. 2005 Apr;79(7):4140-9
15767415
Science. 2005 Mar 4;307(5714):1434-40
15637236
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8198-203
15928092
Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):632-7
14707263
J R Soc Interface. 2005 Dec 22;2(5):489-503
16849208
Trends Ecol Evol. 2007 Jun;22(6):308-15
17337087
J Exp Med. 2009 Jun 8;206(6):1253-72
19487423
Nat Rev Microbiol. 2006 Nov;4(11):865-73
17041633
Science. 1993 Mar 19;259(5102):1749-54
8096089
PLoS Comput Biol. 2007 Oct;3(10):2003-18
17967052
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1862-5
9050870
Science. 2007 Aug 17;317(5840):944-7
17641165
Genetics. 2006 Jun;173(2):589-97
16547114
Science. 1996 Mar 15;271(5255):1582-6
8599114
Nature. 2002 Jul 11;418(6894):144
12110879
Genet Res. 1966 Dec;8(3):269-94
5980116
J Virol. 2005 Nov;79(21):13572-8
16227277
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10758-63
10485899
J Virol. 1993 Apr;67(4):2182-90
8445728
J Virol. 1996 Sep;70(9):6044-53
8709227
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19079-84
18025463
PLoS Comput Biol. 2007 Feb 16;3(2):e29
17305421
Nat Rev Immunol. 2002 Jan;2(1):28-36
11905835
Theor Popul Biol. 2010 May;77(3):189-204
20149814
Cell. 1999 Apr 2;97(1):63-73
10199403
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7
18490657
Genetics. 2005 May;170(1):7-18
15744057
J Virol. 2007 Nov;81(22):12582-95
17728240
J Virol. 1999 Dec;73(12):10489-502
10559367
J Exp Med. 1999 May 17;189(10):1545-54
10330433
J Virol. 2010 Jun;84(12):6096-102
20357090
Genetics. 2002 Apr;160(4):1283-93
11973287
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4204-9
15010526
Antivir Ther. 2004 Apr;9(2):237-46
15134186
Science. 1996 Nov 8;274(5289):985-9
8875941
Science. 2004 Nov 26;306(5701):1547-50
15567861
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14441-6
9826719
J Exp Med. 2009 Jun 8;206(6):1273-89
19487424
J Virol. 2003 Oct;77(20):11193-200
14512567
Nat Rev Genet. 2002 Apr;3(4):252-61
11967550
J Virol. 2004 Aug;78(16):8942-5
15280505