madman
Super Moderator
Abstract
Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as ‘neuroHIV.’ Although combination antiretroviral therapy (cART) has been a tremendous success, in its present form, it cannot eradicate HIV. Reservoirs of virus reside within the central nervous system, serving as sources of HIV virotoxins that damage mitochondria and promote neurotoxicity. Although understudied, there is evidence that HIV or the HIV regulatory protein, trans-activator of transcription (Tat), can dysregulate neurosteroid formation potentially contributing to endocrine dysfunction. People living with HIV commonly suffer from endocrine disorders, including hypercortisolemia accompanied by paradoxical adrenal insufficiency upon stress. Age-related comorbidities often onset sooner and with greater magnitude among people living with HIV and are commonly accompanied by hypogonadism. In the post-cART era, these derangements of the hypothalamic-pituitary-adrenal and -gonadal axes are secondary (i.e., relegated to the brain) and indicative of neuroendocrine dysfunction. We review the clinical and preclinical evidence for neuroendocrine dysfunction in HIV, the capacity for hormone therapeutics to play an ameliorative role, and the future steroid-based therapeutics that may have efficacy as novel adjunctives to cART.
1 | INTRODUCTION
It has been 40 years since the beginning of the HIV pandemic and an estimated 37.6 million people continue to live with the virus worldwide.1 The tremendous success of combination antiretroviral therapy (cART) has increased the life expectancies of people living with HIV (PLWH) and has greatly improved morbidity. However, the transformation of HIV into a chronic care illness has also revealed the long-term consequences of living with the infection. Even in the post-cART era, many individuals continue to suffer from neurological symptoms including an increased prevalence of cognitive impairment, major depression, generalized anxiety disorder, neuropathic pain, and motor dysfunction, collectively referred to as “neuroHIV”.2 Identifying and treating the mechanisms of these neurological deficits is the subject of intense investigation. To this end, the influence of neuroHIV on the neuroendocrine system has become increasingly apparent. In this review, we summarize the recent advances made in our understanding of HIV effects on neuroendocrine function and the potential benefits of steroid-based therapeutics, including the progesterone metabolite, 5α-pregnan3α-ol-20-one (3α,5α-THP or allopregnanolone), on neuroHIV and HIV viremia. Taken together, the data support a reciprocal relationship between HIV and neuroendocrine status, in which HIV dysregulates the neuroendocrine axes, facilitating stress- and age-related comorbidities that neuroendocrine-based therapeutics may help ameliorate.
2 | HIV-MEDIATED NEUROLOGICAL DYSFUNCTION
In the post-cART era, approximately 50% of PLWH suffer from neuroHIV.3 Although cART has reduced the incidence of the most severe form of neurocognitive impairment, HIV-associated dementia (present in ~20% of HIV patients in the pre-cART era vs. ~2% in the post-cART era),3 the proportion of individuals that continue to express any cognitive impairment has remained stable, albeit the symptoms are markedly milder.
2.1 | The HIV central nervous system reservoir
2.2 | Mechanisms of neuroHIV
3 | STEROIDOGENIC DYSREGULATION BY HIV
The endocrine system has long been known to be perturbed by HIV infection with patients presenting with dysfunction of the adrenals, gonads, pituitary, and thyroid.65 However, it is becoming apparent that the interactions between HIV and the endocrine system are dynamic. Endogenous steroids influence HIV replication and neuropathology and, conversely, HIV virotoxins can influence steroid formation. As such, the relationship between neuroendocrine function and neuroHIV symptomatology is reciprocal.
3.1 | Steroid hormones modulate HIV replication
3.2 | Steroid hormones ameliorate HIV-related neuropathology
3.3 | Pregnane steroids ameliorate HIV Tat-induced behavioral pathology
3.4 | HIV disrupts central and circulating steroidogenesis
4 | HIV EFFECTS ON HYPOTHALAMIC-PITUITARY-ADRENAL AND-GONADAL AXES
HIV can exert a profound influence on circulating steroid hormone production. These effects can reduce circulating steroid content via actions at endocrine glands, such as the adrenals or gonads (i.e. primary insufficiency), or via actions targeted to the source of steroid promoting corticotropins and gonadotropins in the hypothalamus and anterior pituitary (i.e. secondary insufficiency). The latter is far more common in the post-cART era, emphasizing the need for HIV therapeutics with efficacy in the CNS. As a result, PLWH is commonly affected by disruptions to the hypothalamic-pituitary-adrenal (HPA) and –gonadal (HPG) axes.91,92 Such dysfunction likely contributes to the neuropsychiatric components of neuroHIV and the age-related comorbidities that are observed earlier in life and to a greater magnitude among PLWH.
4.1 | HPA stress axis dysregulation in people living with HIV
4.2 | Potential mechanisms involved in HIV dysregulation of the HPA axis
4.3 | HPG stress axis dysregulation in people living with HIV
4.4 | Potential mechanisms involved in HIV dysregulation of the HPG axis
5 | STEROID-BASED THERAPEUTICS FOR THE TREATMENT OF HIV
5.1 | Novel adjunct therapeutics for HIV suppression
Antiretroviral therapeutics have dramatically increased the life expectancy of PLWH. However, these drugs are not able to eradicate the virus, nor neuroHIV, given that they cannot target reservoirs such as those within the CNS and do not target certain virotoxins such as Tat. It is notable that several promising leads are based on a steroid scaffold. Most notably, didehydro-cortistatin A (dCA), an analog of a steroid-like alkaloid obtained from marine sponge, is demonstrated in vitro to bind to the Tat-TAR complex, blocking HIV replication without producing cellular toxicity, to attenuate HIV-mediated cytokine expression, and to inhibit behavioral effects promoted by Tat in vivo. 185,186 dCA was found to selectively bind the unstructured basic region of Tat.187 A combination of dCA and cART suppressed active HIV viral replication, reactivation, and rebound of the latent viral reservoir.188 Additional chemical derivatives of dCA were sought to rationalize their ability to dock at specific binding sites of the Tat protein.187 Given the ability of dCA to inhibit Tat expression during early viral replication and penetrate latent viral reservoirs in the brain with good bioavailability, dCA and its novel steroidal-based analogs hold potential as future cART adjuncts.187-189
Additional estrogen-based therapeutics have also been identified, including selective estrogen receptor β agonists, such as (S)- equol and several phytoestrogens. (S)-equol improved sensorimotor gating and motivational deficits in HIV transgenic rats190-192 and prevented combined cocaine and HIV-mediated synaptopathy.193 The phytoestrogens, daidzein, and liquiritigenin, restored Tat-mediated synaptodendritic recovery.194 Our own work has focused on the potential therapeutic advantages of neurosteroids.
Neurosteroids are synthesized de novo in the brain from cholesterol195 and can also reach the brain from peripheral sources such as the adrenals and gonads.196 AlloP is perhaps the most well-characterized neurosteroid with a pharmacodynamic profile that is suitable for potentially offsetting the effects of HIV Tat (Figure 1). Given the excitotoxic profile exerted by Tat, the actions of AlloP as a potent positive allosteric modulator of GABAA receptors are expected to reinstate excitatory-inhibitory balance via the influx of Cl−. Moreover, AlloP may act as an antagonist of L-type Ca2+ channels,197,198 further attenuating the excitotoxic actions of Tat. We have seen promising evidence for AlloP to offset Tat-mediated neurotoxicity in vitro (Figure 2) and to attenuate Tat-mediated behavioral interactions with opioids in vivo. 81 Although AlloP is a small molecule that readily crosses the blood-brain barrier and is well-tolerated,199 it is also rapidly re-distributed from the brain, accumulates in adipose tissue, and has a short elimination half-life.200,201 As such, we are currently working to synthesize AlloP analogs with anti-Tat and anti-viremic properties. A ligand structural alignment of dCA, (S)- Equol, and AlloP reveals structural similarities that may help explain their anti-HIV activities (Figure 6). For example, both terminal ends of the molecules contain polar elements (oxygen or a nitrogen atom). Induced-fit docking of dCA in the NMR-derived structure of Tat (Protein Data Bank: 1K5K) reveals important hydrogen bonding interactions between dCA and the R49 and R52 residues, which are part of the identified motif (the ARM domain) (Figure 7). Induced-fit docking of AlloP in this binding site also reveals important hydrogen bonding interactions between AlloP and the R49 residue, in addition to strong hydrophobic interactions (Figure 7). These preliminary data suggest that dCA and AlloP may target a shared Tat binding site that may partly underlie their potential anti-Tat efficacy. In light of this, the development of novel AlloP analogs may hold promise with respect to potential future cART adjunctive therapeutics.
Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as ‘neuroHIV.’ Although combination antiretroviral therapy (cART) has been a tremendous success, in its present form, it cannot eradicate HIV. Reservoirs of virus reside within the central nervous system, serving as sources of HIV virotoxins that damage mitochondria and promote neurotoxicity. Although understudied, there is evidence that HIV or the HIV regulatory protein, trans-activator of transcription (Tat), can dysregulate neurosteroid formation potentially contributing to endocrine dysfunction. People living with HIV commonly suffer from endocrine disorders, including hypercortisolemia accompanied by paradoxical adrenal insufficiency upon stress. Age-related comorbidities often onset sooner and with greater magnitude among people living with HIV and are commonly accompanied by hypogonadism. In the post-cART era, these derangements of the hypothalamic-pituitary-adrenal and -gonadal axes are secondary (i.e., relegated to the brain) and indicative of neuroendocrine dysfunction. We review the clinical and preclinical evidence for neuroendocrine dysfunction in HIV, the capacity for hormone therapeutics to play an ameliorative role, and the future steroid-based therapeutics that may have efficacy as novel adjunctives to cART.
1 | INTRODUCTION
It has been 40 years since the beginning of the HIV pandemic and an estimated 37.6 million people continue to live with the virus worldwide.1 The tremendous success of combination antiretroviral therapy (cART) has increased the life expectancies of people living with HIV (PLWH) and has greatly improved morbidity. However, the transformation of HIV into a chronic care illness has also revealed the long-term consequences of living with the infection. Even in the post-cART era, many individuals continue to suffer from neurological symptoms including an increased prevalence of cognitive impairment, major depression, generalized anxiety disorder, neuropathic pain, and motor dysfunction, collectively referred to as “neuroHIV”.2 Identifying and treating the mechanisms of these neurological deficits is the subject of intense investigation. To this end, the influence of neuroHIV on the neuroendocrine system has become increasingly apparent. In this review, we summarize the recent advances made in our understanding of HIV effects on neuroendocrine function and the potential benefits of steroid-based therapeutics, including the progesterone metabolite, 5α-pregnan3α-ol-20-one (3α,5α-THP or allopregnanolone), on neuroHIV and HIV viremia. Taken together, the data support a reciprocal relationship between HIV and neuroendocrine status, in which HIV dysregulates the neuroendocrine axes, facilitating stress- and age-related comorbidities that neuroendocrine-based therapeutics may help ameliorate.
2 | HIV-MEDIATED NEUROLOGICAL DYSFUNCTION
In the post-cART era, approximately 50% of PLWH suffer from neuroHIV.3 Although cART has reduced the incidence of the most severe form of neurocognitive impairment, HIV-associated dementia (present in ~20% of HIV patients in the pre-cART era vs. ~2% in the post-cART era),3 the proportion of individuals that continue to express any cognitive impairment has remained stable, albeit the symptoms are markedly milder.
2.1 | The HIV central nervous system reservoir
2.2 | Mechanisms of neuroHIV
3 | STEROIDOGENIC DYSREGULATION BY HIV
The endocrine system has long been known to be perturbed by HIV infection with patients presenting with dysfunction of the adrenals, gonads, pituitary, and thyroid.65 However, it is becoming apparent that the interactions between HIV and the endocrine system are dynamic. Endogenous steroids influence HIV replication and neuropathology and, conversely, HIV virotoxins can influence steroid formation. As such, the relationship between neuroendocrine function and neuroHIV symptomatology is reciprocal.
3.1 | Steroid hormones modulate HIV replication
3.2 | Steroid hormones ameliorate HIV-related neuropathology
3.3 | Pregnane steroids ameliorate HIV Tat-induced behavioral pathology
3.4 | HIV disrupts central and circulating steroidogenesis
4 | HIV EFFECTS ON HYPOTHALAMIC-PITUITARY-ADRENAL AND-GONADAL AXES
HIV can exert a profound influence on circulating steroid hormone production. These effects can reduce circulating steroid content via actions at endocrine glands, such as the adrenals or gonads (i.e. primary insufficiency), or via actions targeted to the source of steroid promoting corticotropins and gonadotropins in the hypothalamus and anterior pituitary (i.e. secondary insufficiency). The latter is far more common in the post-cART era, emphasizing the need for HIV therapeutics with efficacy in the CNS. As a result, PLWH is commonly affected by disruptions to the hypothalamic-pituitary-adrenal (HPA) and –gonadal (HPG) axes.91,92 Such dysfunction likely contributes to the neuropsychiatric components of neuroHIV and the age-related comorbidities that are observed earlier in life and to a greater magnitude among PLWH.
4.1 | HPA stress axis dysregulation in people living with HIV
4.2 | Potential mechanisms involved in HIV dysregulation of the HPA axis
4.3 | HPG stress axis dysregulation in people living with HIV
4.4 | Potential mechanisms involved in HIV dysregulation of the HPG axis
5 | STEROID-BASED THERAPEUTICS FOR THE TREATMENT OF HIV
5.1 | Novel adjunct therapeutics for HIV suppression
Antiretroviral therapeutics have dramatically increased the life expectancy of PLWH. However, these drugs are not able to eradicate the virus, nor neuroHIV, given that they cannot target reservoirs such as those within the CNS and do not target certain virotoxins such as Tat. It is notable that several promising leads are based on a steroid scaffold. Most notably, didehydro-cortistatin A (dCA), an analog of a steroid-like alkaloid obtained from marine sponge, is demonstrated in vitro to bind to the Tat-TAR complex, blocking HIV replication without producing cellular toxicity, to attenuate HIV-mediated cytokine expression, and to inhibit behavioral effects promoted by Tat in vivo. 185,186 dCA was found to selectively bind the unstructured basic region of Tat.187 A combination of dCA and cART suppressed active HIV viral replication, reactivation, and rebound of the latent viral reservoir.188 Additional chemical derivatives of dCA were sought to rationalize their ability to dock at specific binding sites of the Tat protein.187 Given the ability of dCA to inhibit Tat expression during early viral replication and penetrate latent viral reservoirs in the brain with good bioavailability, dCA and its novel steroidal-based analogs hold potential as future cART adjuncts.187-189
Additional estrogen-based therapeutics have also been identified, including selective estrogen receptor β agonists, such as (S)- equol and several phytoestrogens. (S)-equol improved sensorimotor gating and motivational deficits in HIV transgenic rats190-192 and prevented combined cocaine and HIV-mediated synaptopathy.193 The phytoestrogens, daidzein, and liquiritigenin, restored Tat-mediated synaptodendritic recovery.194 Our own work has focused on the potential therapeutic advantages of neurosteroids.
Neurosteroids are synthesized de novo in the brain from cholesterol195 and can also reach the brain from peripheral sources such as the adrenals and gonads.196 AlloP is perhaps the most well-characterized neurosteroid with a pharmacodynamic profile that is suitable for potentially offsetting the effects of HIV Tat (Figure 1). Given the excitotoxic profile exerted by Tat, the actions of AlloP as a potent positive allosteric modulator of GABAA receptors are expected to reinstate excitatory-inhibitory balance via the influx of Cl−. Moreover, AlloP may act as an antagonist of L-type Ca2+ channels,197,198 further attenuating the excitotoxic actions of Tat. We have seen promising evidence for AlloP to offset Tat-mediated neurotoxicity in vitro (Figure 2) and to attenuate Tat-mediated behavioral interactions with opioids in vivo. 81 Although AlloP is a small molecule that readily crosses the blood-brain barrier and is well-tolerated,199 it is also rapidly re-distributed from the brain, accumulates in adipose tissue, and has a short elimination half-life.200,201 As such, we are currently working to synthesize AlloP analogs with anti-Tat and anti-viremic properties. A ligand structural alignment of dCA, (S)- Equol, and AlloP reveals structural similarities that may help explain their anti-HIV activities (Figure 6). For example, both terminal ends of the molecules contain polar elements (oxygen or a nitrogen atom). Induced-fit docking of dCA in the NMR-derived structure of Tat (Protein Data Bank: 1K5K) reveals important hydrogen bonding interactions between dCA and the R49 and R52 residues, which are part of the identified motif (the ARM domain) (Figure 7). Induced-fit docking of AlloP in this binding site also reveals important hydrogen bonding interactions between AlloP and the R49 residue, in addition to strong hydrophobic interactions (Figure 7). These preliminary data suggest that dCA and AlloP may target a shared Tat binding site that may partly underlie their potential anti-Tat efficacy. In light of this, the development of novel AlloP analogs may hold promise with respect to potential future cART adjunctive therapeutics.
