HIV-1 Capsid-Targeting Domain of Cleavage and Polyadenylation Specificity Factor 6

Lee, Kyeong Eun; Mulky, Alok; Yuen, Wendy; Martin, Thomas; Meyerson, Nicholas R.; Choi, Laura; Yu, Hyun; Sawyer, Sara L.; KewalRamani, Vineet N.

doi:10.1128/jvi.06607-11

Cited by 68 publications

(91 citation statements)

References 40 publications

(49 reference statements)

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“…CA must maintain a stable structure that can adopt a range of CA-CA interactions that are finely tuned and able to adjust as virions assemble and disassemble into immature and mature configurations (58-61). Moreover, CA must also form interactions with a wide variety of host proteins (62)(63)(64). While IN forms critical interactions with LEDGF (65,66), as well as interactions with TRN-SR2(TNPO3) (35,67) and INI-1/hSNF5 (36,68), and also undergoes multimerization processes (21,(69)(70)(71), the larger number of specialized CA-CA interactions that mediate accurate virion assembly may make CA exceptionally fragile (Fig.…”

Section: Discussionmentioning

confidence: 99%

Uneven Genetic Robustness of HIV-1 Integrase

Rihn

Hughes

Wilson

et al. 2015

J Virol

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Genetic robustness (tolerance of mutation) may be a naturally selected property in some viruses, because it should enhance adaptability. Robustness should be especially beneficial to viruses like HIV-1 that exhibit high mutation rates and exist in immunologically hostile environments. Surprisingly, however, the HIV-1 capsid protein (CA) exhibits extreme fragility. To determine whether fragility is a general property of HIV-1 proteins, we created a large library of random, single-amino-acid mutants in HIV-1 integrase (IN), covering >40% of amino acid positions. Despite similar degrees of sequence variation in naturally occurring IN and CA sequences, we found that HIV-1 IN was significantly more robust than CA, with random nonsilent IN mutations only half as likely to cause lethal defects. Interestingly, IN and CA were similar in that a subset of mutations with high in vitro fitness were rare in natural populations. IN mutations of this type were more likely to occur in the buried interior of the modeled HIV-1 intasome, suggesting that even very subtle fitness effects suppress variation in natural HIV-1 populations. Lethal mutations, in particular those that perturbed particle production, proteolytic processing, and particle-associated IN levels, were strikingly localized at specific IN subunit interfaces. This observation strongly suggests that binding interactions between particular IN subunits regulate proteolysis during HIV-1 virion morphogenesis. Overall, use of the IN mutant library in conjunction with structural models demonstrates the overall robustness of IN and highlights particular regions of vulnerability that may be targeted in therapeutic interventions. IMPORTANCEThe HIV-1 integrase (IN) protein is responsible for the integration of the viral genome into the host cell chromosome. To measure the capacity of IN to maintain function in the face of mutation, and to probe structure/function relationships, we created a library of random single-amino-acid IN mutations that could mimic the types of mutations that naturally occur during HIV-1 infection. Previously, we measured the robustness of HIV-1 capsid in this manner and determined that it is extremely intolerant of mutation. In contrast to CA, HIV-1 IN proved relatively robust, with far fewer mutations causing lethal defects. However, when we subsequently mapped the lethal mutations onto a model of the structure of the multisubunit IN-viral DNA complex, we found the lethal mutations that caused virus morphogenesis defects tended to be highly localized at subunit interfaces. This discovery of vulnerable regions of HIV-1 IN could inform development of novel therapeutics.

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Section: Discussionmentioning

confidence: 99%

Uneven Genetic Robustness of HIV-1 Integrase

Rihn

Hughes

Wilson

et al. 2015

J Virol

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“…HIV-1 CA containing an N74D substitution circumvented the inhibition of HIV-1 infection, which was seen during TNPO3 knockdown (19,21,70). However, it is not clear from these studies whether CA and TNPO3 interact directly or if their interactions are mediated by another factor(s).…”

Section: Tnpo3 Does Not Interact Directly With Ca Tubes In Vitro-mentioning

confidence: 94%

“…Several studies have implicated CA as a primary determinant of HIV-1 dependence on TNPO3 (19,21,70). HIV-1 CA containing an N74D substitution circumvented the inhibition of HIV-1 infection, which was seen during TNPO3 knockdown (19,21,70).…”

Section: Tnpo3 Does Not Interact Directly With Ca Tubes In Vitro-mentioning

confidence: 99%

“…One possibility is that the N74D substitution alters interplay between CA and another factor, which in turn directly or indirectly links this protein-protein complex to TNPO3. For example, CPSF-6 has been shown to interact with wild type and not N74D CA (21,70). Furthermore, a recent study (70) has mapped a small CPSF-6 segment of amino acids 314 -322 that directly engages wild type CA.…”

Section: Tnpo3 Does Not Interact Directly With Ca Tubes In Vitro-mentioning

confidence: 99%

“…For example, CPSF-6 has been shown to interact with wild type and not N74D CA (21,70). Furthermore, a recent study (70) has mapped a small CPSF-6 segment of amino acids 314 -322 that directly engages wild type CA. At its C terminus (amino acids 527-588) CPSF-6 contains an SR domain, which is a potential cargo of TNPO3 (71) and, therefore, likely to mediate the (41) analysis with a total estimate value of 0.91.…”

Section: Tnpo3 Does Not Interact Directly With Ca Tubes In Vitro-mentioning

confidence: 99%

See 2 more Smart Citations

Interaction of the HIV-1 Intasome with Transportin 3 Protein (TNPO3 or TRN-SR2)

Larue

Gupta

Wuensch

et al. 2012

Journal of Biological Chemistry

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Background: TNPO3 is a key cellular factor involved in early steps of HIV-1 replication. Results: TNPO3 is highly structured, interacts with the HIV-1 intasome by engaging the C-terminal domain of integrase, and does not directly bind capsid tubes. Conclusion: TNPO3 interacts with HIV-1 intasomes and not capsid cores. Significance: Our findings aid future genetic analysis to elucidate the role of TNPO3 in HIV-1 replication.

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Keeping your armour intact: How HIV‐1 evades detection by the innate immune system

2014

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HIV-1 infects dendritic cells (DCs) without triggering an effective innate antiviral immune response. As a consequence, the induction of adaptive immune responses controlling virus spread is limited. In a recent issue of Immunity, Lahaye and colleagues show that intricate interactions of HIV capsid with the cellular cofactor cyclophilin A (CypA) control infection and innate immune activation in DCs. Manipulation of HIV-1 capsid to increase its affinity for CypA results in reduced virus infectivity and facilitates access of the cytosolic DNA sensor cGAS to reverse transcribed DNA. This in turn induces a strong host response. Here, we discuss these findings in the context of recent developments in innate immunity and consider the implications for disease control and vaccine design.

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HIV-1 Capsid-Targeting Domain of Cleavage and Polyadenylation Specificity Factor 6

Cited by 68 publications

References 40 publications

Uneven Genetic Robustness of HIV-1 Integrase

Uneven Genetic Robustness of HIV-1 Integrase

Interaction of the HIV-1 Intasome with Transportin 3 Protein (TNPO3 or TRN-SR2)

Keeping your armour intact: How HIV‐1 evades detection by the innate immune system

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