药学学报 Acta Pharmaceutica Sinica 2010, 45 (2): 165−176
· 165 ·
The development of anti-HIV-1 drugs
LU Xiao-fan1, CHEN Zhi-wei1, 2*
(1. AIDS Institute, 2. Department of Microbiology and Research Center of Infection and Immunology,
Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China)
Abstract: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodefi-
ciency disease syndrome (AIDS). After over 26 years of efforts, there is still not a therapeutic cure or an effec-
tive vaccine against HIV/AIDS. The clinical management of HIV-1 infected people largely relies on antiretro-
viral therapy (ART). Although highly active antiretroviral therapy (HAART) has provided an effective way to
treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of
drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs.
Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are
in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors,
NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibi-
tors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists). Here, we intend to provide updated
information of currently available antiretroviral drugs for ART to promote the development of novel anti-HIV-1
Key words: HIV-1; AIDS; antiretroviral drug; antiretroviral therapy; highly active antiretroviral therapy
CLC number: R916 Document code: A Article ID: 0513-4870 (2010) 02-0165-12
Since acquired immunodeficiency disease syn-
drome (AIDS) was first recognized in 1981, the lack of
an effective vaccine remains a major obstacle in the
battle against the human immunodeficiency virus type
1 (HIV-1) pandemic. Although current antiretroviral
therapy (ART) does not provide a cure, it has made
AIDS a manageable disease by decreasing the mortality
and extending the life span of infected patients,
especially in developed countries. With the increasing
burden of ART in developing countries, together with
the frequent emergence of drug resistant viruses among
treated people, development of the most effective ART
is one of the greatest challenges in this battle[1, 2].
An antiretroviral (ARV) drug works by interrupting
one of the critical steps in the HIV-1 life cycle (Figure
1). Zidovudine (AZT), a byproduct of anti-cancer
research activities, was the first anti-HIV-1 drug identi-
fied to block viral reverse transcriptase. AZT is now
classified as a nucleoside reverse transcriptase inhibitor
Project supported by HKU-UDF, HKSARG FHB/RFCID09080772 and
the National Basic Research Program of China
(2008ZX10001-011 and 2008ZX10001-015)
*Corresponding author Tel: 86-852-28199831, Fax: 86-852-28177805,
(NRTI). It has been used for AIDS treatment since
1987. Since then, efforts on the understanding of
the HIV-1 life cycle and pathogenesis have greatly
enhanced the outputs of HIV-1 drug discoveries. As a
landmark of modern medicine, 24 additional antiretro-
virals (ARVs) have been developed for clinical use after
AZT. No second human disease is comparable to
HIV/AIDS in this regard. These ARVs can be divided
into four classes including reverse transcriptase
inhibitors (RTIs) (e.g. nucleoside reverse transcriptase
inhibitors, NRTIs; and non-nucleoside reverse tran-
scriptase inhibitors, NNRTIs), protease inhibitors (PIs),
integrase inhibitors and entry inhibitors (e.g. fusion
inhibitors and CCR5 antagonists).
It should be emphasized that highly active antire-
troviral therapy (HAART) has been the major accom-
plishment for the chronic suppression of HIV-1 replica-
tion in patients since 1996. The reason why AIDS
has become a treatable disease is largely relied on
HAART. By targeting multiple steps of the HIV-1
life cycle, HAART results in undetectable viral load,
delayed emergence of drug resistant viral variants and
gradual recovery of CD4+ T cells in infected patients.
HAART works remarkably well at controlling the virus
· 166 ·
药学学报 Acta Pharmaceutica Sinica 2010, 45 (2): 165−176
Figure 1 The life cycle of HIV-1. 1. HIV-1 gp120 binds to CD4 and co-receptor CCR5/CXCR4 on target cell; 2. HIV-1 gp41 mediates
fusion with target cell; 3. Nucleocapsid containing viral genome and enzymes enters cells; 4. Viral genome and enzymes are released;
5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-DNA hybrids; 6. RNA template is degraded by
ribonuclease H followed by the synthesis of HIV dsDNA; 7. Viral dsDNA is transported into the nucleus and integrated into the host
chromosomal DNA by the viral integrase enzyme; 8. Transcription of proviral DNA into genomic ssRNA and mRNAs formation after
processing; 9. Viral RNA is exported to cytoplasm; 10. Synthesis of viral precursor proteins under the catalysis of host-cell ribosomes;
11. Viral protease cleaves the precursors into viral proteins; 12. HIV ssRNA and proteins assemble under host cell membrane, into which
gp120 and gp41 are inserted; 13. Membrane of host-cell buds out, forming the viral envelope; 14. Matured viral particle is released
(e.g. a newly HIV-infected 20-year-old who receives
appropriate treatment has a life expectancy of at least
69 years). Unfortunately, HIV-1 cannot be eradicated
completely by current HAART due to the existence
of the latent viral reservoirs[3,
HAART have to remain on treatment throughout their
lifetime, and thus, will need to deal with issues related
to the accumulated side effects of drugs and emergence
of drug resistant viruses.
Due to the toxicity and cost of ARVs, clinicians
tend to delay the initiation of HAART until a person’s
health begins to decline. In particular, because the
availability of ARVs is severely limited in developing
countries, some guidelines were devised so that therapy
would not be administered until a person developed
AIDS. HIV-1 infection, however, is likely to be
much more toxic than any ARVs. Recently, there was
a chorus of support for sustaining and increasing the
availability of HAART and initiating treatment earlier
in the course of HIV-1 infection in order to save lives
and prevent new infections from occurring. Evidence
is accumulating that suggests starting therapy much
earlier in the course of HIV-1 infection may be
beneficial, which adds additional burden on ARV
7]. People receiving
supply and new drug discoveries.
1 Reverse transcriptase inhibitors
HIV-1 reverse transcriptase (RT) was the first
target for ARV development. As a multifunctional
enzyme, RT processes the synthesis of double-stranded
proviral DNA by using single-stranded RNA as a
template upon viral entry into host cells. RT is
encoded by the HIV-1 pol gene. The matured RT is a
heterodimer composed of the p66 and p51 subunits.
These two subunits share a common N-terminal sub-
domain, named as fingers, palm, thumb and connection
(Figure 2), and a RNase H domain in p66 subunit[9, 10].
The site of DNA polymerase activity situates in the
palm sub-domain of the p66 subunit. This activity site
includes three aspartic acid residues at positions 110,
185 and 186, serving as the binding site for dNTPs.
1.1 Nucleoside reverse transcriptase inhibitors
(NRTIs) NRTIs were the first class of ARVs used
in the HIV/AIDS therapy. NRTIs include nucleoside
and nucleotide RTIs. They are the modified form of
cellular nucleosides. After entry into the cells and
undergoing intracellular phosphorylation, they can be
incorporated into the evolving DNA chain under the
action of RT[12,
13]. NRTIs act by competing with natural
LU Xiao-fan, et al: The development of anti-HIV-1 drugs
· 175 ·
5", 3'-(2', 5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl)))-
3-ethylthy mine [J]. Biochemistry, 2000, 39: 1427−1433.
 Sluis-Cremer N, Arion D, Parniak MA. Destabilization of the
HIV-1 reverse transcriptase dimer upon interaction with N-acyl
hydrazone inhibitors [J]. Mol Pharmacol, 2002, 62: 398−405.
 Creagh T, Ruckle JL, Tolbert DT, et al. Safety and pharma-
cokinetics of single doses of (+)-calanolide A, a novel,
naturally occurring nonnucleoside reverse transcriptase inhibitor,
in healthy, human immunodeficiency virus-negative human
subjects [J]. Antimicrob Agents Chemother, 2001, 45: 1379−
 Ma T, Gao Q, Chen Z, et al. Chemical resolution of +/− -
calanolide A, +/− -cordatolide A and their 11-demethyl analogues
[J]. Bioorg Med Chem Lett, 2008, 18: 1079−1083.
 Ma T, Liu L, Xue H, et al. Chemical library and structure-
activity relationships of 11-demethyl-12-oxo calanolide A
analogues as anti-HIV-1 agents [J]. J Med Chem, 2008, 51:
 Goebel F, Yakovlev A, Pozniak AL, et al. Short-term antiviral
activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-
infected subjects [J]. AIDS, 2006, 20: 1721−1726.
 Anderson J, Schiffer C, Lee SK, et al. Antiviral Strategies
V189 [M]. Berlin: Springer, 2009: 85−110.
 Wensing AM, van Maarseveen NM, Nijhuis M. Fifteen years
of HIV protease inhibitors: raising the barrier to resistance [J].
Antiviral Res, 2010, 85: 59−74.
 Craig JC, Duncan IB, Hockley D, et al. Antiviral properties
of Ro 31-8959, an inhibitor of human immunodeficiency virus
(HIV) proteinase [J]. Antiviral Res, 1991, 16: 295−305.
 Jacobsen H, Yasargil K, Winslow DL, et al. Characterization
of human immunodeficiency virus type 1 mutants with decreased
sensitivity to proteinase inhibitor Ro 31-8959 [J]. Virology,
1995, 206: 527−534.
 Turriziani O, Antonelli G, Jacobsen H, et al. Identification
of an amino acid substitution involved in the reduction of
sensitivity of HIV-1 to an inhibitor of viral proteinase [J].
Acta Virol, 1994, 38: 297−298.
 Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic
enhancement of inhibitors of the human immunodeficiency
virus protease by coadministration with ritonavir [J]. Anti-
microb Agents Chemother, 1997, 41: 654−660.
 Vacca JP, Dorsey BD, Schleif WA, et al. L-735,524: an orally
bioavailable human immunodeficiency virus type 1 protease
inhibitor [J]. Proc Natl Acad Sci USA, 1994, 91: 4096−4100.
 Condra JH, Holder DJ, Schleif WA, et al. Genetic correlates
of in vivo viral resistance to indinavir, a human immunodefi-
ciency virus type 1 protease inhibitor [J]. J Virol, 1996, 70:
 Kaldor SW, Kalish VJ, Davies JF 2nd, et al. Viracept
(nelfinavir mesylate, AG1343): a potent, orally bioavailable
inhibitor of HIV-1 protease [J]. J Med Chem, 1997, 40:
 Robinson BS, Riccardi KA, Gong YF, et al. BMS-232632, a
highly potent human immunodeficiency virus protease inhibitor
that can be used in combination with other available antiretroviral
agents [J]. Antimicrob Agents Chemother, 2000, 44: 2093−
 Johnson M. Response to "Atazanavir/ritonavir versus lopinavir/
ritonavir: equivalent or different efficacy profiles?" by Hill [J].
AIDS, 2006, 20: 1987.
 Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-
daily atazanavir with efavirenz, each in combination with
fixed-dose zidovudine and lamivudine, as initial therapy for
patients infected with HIV [J]. J Acquir Immune Defic Syndr,
2004, 36: 1011−1019.
 Rodriguez-French A, Boghossian J, Gray GE, et al. The
NEAT study: a 48-week open-label study to compare the
antiviral efficacy and safety of GW433908 versus nelfinavir in
antiretroviral therapy-naive HIV-1-infected patients [J]. J
Acquir Immune Defic Syndr, 2004, 35: 22−32.
 Gathe J, Cooper DA, Farthing C, et al. Efficacy of the protease
inhibitors tipranavir plus ritonavir in treatment-experienced
patients: 24-week analysis from the RESIST-1 trial [J]. Clin
Infect Dis, 2006, 43: 1337−1346.
 Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/
ritonavir-based regimen is noninferior to twice-daily dosing
and results in similar safety and tolerability in antiretroviral-
naive subjects through 48 weeks [J]. J Acquir Immune Defic
Syndr, 2009, 50: 474−481.
 De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel
human immunodeficiency virus type 1 protease inhibitor active
against protease inhibitor-resistant viruses, including a broad
range of clinical isolates [J]. Antimicrob Agents Chemother,
2005, 49: 2314−2321.
 Degoey DA, Grampovnik DJ, Flentge CA, et al. 2-Pyridyl
P1'-substituted symmetry-based human immunodeficiency
virus protease inhibitors (A-792611 and A-790742) with
potential for convenient dosing and reduced side effects [J].
J Med Chem, 2009, 52: 2571−2586.
 Nair V, Chi G. HIV integrase inhibitors as therapeutic agents
in AIDS [J]. Rev Med Virol, 2007, 17: 277−295.
 Tilton JC, Doms RW. Entry inhibitors in the treatment of
· 176 ·
药学学报 Acta Pharmaceutica Sinica 2010, 45 (2): 165−176
HIV-1 infection [J]. Antiviral Res, 2010, 85: 91−100.
 Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with
optimized background therapy for resistant HIV-1 infection [J].
N Engl J Med, 2008, 359: 339−354.
 Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and
efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518)
in treatment-experienced patients with multidrug-resistant virus:
a phase II randomised controlled trial [J]. Lancet, 2007, 369:
 Klibanov OM. Elvitegravir, an oral HIV integrase inhibitor,
for the potential treatment of HIV infection [J]. Curr Opin
Investig Drugs, 2009, 10: 190−200.
 Shimura K, Kodama EN. Elvitegravir: a new HIV integrase
inhibitor [J]. Antivir Chem Chemother, 2009, 20: 79−85.
 Marinello J, Marchand C, Mott BT, et al. Comparison of
raltegravir and elvitegravir on HIV-1 integrase catalytic reactions
and on a series of drug-resistant integrase mutants [J]. Bio-
chemistry, 2008, 47:9345-9354.
 Sayana S, Khanlou H. Maraviroc: a new CCR5 antagonist [J].
Expert Rev Anti Infect Ther, 2009, 7: 9−19.
 Mascolini M. Epidemic (and lesser) lessons from Rio Centro.
Part 1. The inversions. 3rd IAS Conference on HIV Pathogenesis
and Treatment. July 24-27, 2005, Rio de Janeiro [J]. IAPAC
Mon, 2005, 11: 300−5, 310−9.
 Kummerle T, Lehmann C, Hartmann P, et al. Vicriviroc: a
CCR5 antagonist for treatment-experienced patients with HIV-1
infection [J]. Expert Opin Investig Drugs, 2009, 18: 1773−
《药学学报》入选 WHO 西太平洋地区医学索引 (WPRIM)
2009 年 12 月, 经过本刊编辑部申请, 以及 WHO 西太平洋地区医学索引 (The Western Pacific Region
Index Medicus, WPRIM) 中国生物医学期刊评审委员会评审, 并经 WPRIM 期刊评审委员会审核, 《药学学
为了促进卫生信息的全球共享与利用, 世界卫生组织 (WHO) 于 2005 年启动了全球卫生图书馆
(Global Health Library, GHL) 项目, 拟建立基于互联网的卫生虚拟图书馆, 旨在便捷地向全世界提供卫生
相关信息。 GHL 的一项重要内容是建立全球医学索引 (Global Index Medicus, GIM) , 提供全世界的医学文
献题录及文摘。WPRIM 是 GHL 项目的一个重要组成部分, 主要收录 WHO 西太平洋各成员国和地区所出
版的覆盖卫生、 生物医学领域的期刊及灰色文献的题录 (包括文摘) 信息。 WPRIM 检索服务平台将于 2010
年 5 月正式开通。
2010 年 1 月